TW202045495A - Crystalline form of 1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-n-(2-(trifluoromethyl)pyridin-4-yl)-1h-pyrazole-4-carboxamide monohydrate - Google Patents

Crystalline form of 1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-n-(2-(trifluoromethyl)pyridin-4-yl)-1h-pyrazole-4-carboxamide monohydrate Download PDF

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TW202045495A
TW202045495A TW109105620A TW109105620A TW202045495A TW 202045495 A TW202045495 A TW 202045495A TW 109105620 A TW109105620 A TW 109105620A TW 109105620 A TW109105620 A TW 109105620A TW 202045495 A TW202045495 A TW 202045495A
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卡莉娜 雷茲
克里斯托弗 金普
羅伯特 吉爾特曼
魏昊娟
周鵬
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比利時商健生藥品公司
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    • C—CHEMISTRY; METALLURGY
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C—CHEMISTRY; METALLURGY
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    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Abstract

The present invention relates to a crystalline form of 1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-N-[2-(trifluoromethyl)pyridin-4-yl]-1H-pyrazole-4-carboxamide (Compound A) monohydrate, and processes for preparation thereof. The crystalline form and compositions thereof are useful in the treatment of MALT-1 related diseases.

Description

1-(1-側氧基-1,2-二氫異喹啉-5-基)-5-(三氟甲基)-N-(2-(三氟甲基)吡啶-4-基)-1H-吡唑-4-甲醯胺一水合物的結晶形式 1-(1-Pendant oxy-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-N-(2-(trifluoromethyl)pyridin-4-yl) The crystalline form of -1H-pyrazole-4-methamide monohydrate

本發明關於1-(1-側氧基-1,2-二氫異喹啉-5-基)-5-(三氟甲基)-N-[2-(三氟甲基)吡啶-4-基]-1H-吡唑-4-甲醯胺(化合物A)一水合物的結晶形式。該結晶形式可用於治療疾病、綜合症、病症或障礙，特別是MALT1相關的疾病、綜合症、病症或障礙，包括但不限於癌症和免疫性疾病。本發明還關於包含這種結晶形式的藥物組成物，製備這種結晶形式之方法，以及這種結晶形式或藥物組成物用於治療與MALT1抑制劑相關的癌症和自體免疫性疾病、綜合症、障礙或病症之用途。 The present invention relates to 1-(1-side oxy-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl) -N -[2-(trifluoromethyl)pyridine-4 -Yl]-1 H -pyrazole-4-carboxamide (Compound A) in the crystalline form of the monohydrate. The crystalline form can be used to treat diseases, syndromes, disorders or disorders, especially MALT1 related diseases, syndromes, disorders or disorders, including but not limited to cancer and immune diseases. The present invention also relates to a pharmaceutical composition comprising this crystalline form, a method for preparing this crystalline form, and the use of this crystalline form or pharmaceutical composition for the treatment of cancer and autoimmune diseases and syndromes associated with MALT1 inhibitor , Obstacles or illnesses.

MALT1(黏膜相關淋巴組織淋巴瘤易位1)係經典NFKB傳訊途徑的關鍵介體。MALT1係唯一的人類副胱天蛋白酶(paracaspase)，且轉導來自B細胞受體(BCR)和T細胞受體(TCR)的信號。MALT1係受體激活後形成的CBM複合物的活性亞基。該CBM複合物由三種蛋白質的多個亞基組成：CARD11(胱天蛋白酶募集結構域家族成員11)、BCL10(B細胞CLL/淋巴瘤10) 和MALT1。MALT1藉由兩種機制影響NFKB傳訊：首先，MALT1起支架蛋白的作用並募集NFKB傳訊蛋白，例如TRAF6、TAB-TAK1或NEMO-IKKα/β；其次，作為半胱胺酸蛋白酶的MALT1切割並由此滅活NFKB傳訊的負調控因子，例如RelB、A20或CYLD。MALT1活性的最終端點係FKB轉錄因子複合物的核易位和FKB傳訊的激活(Jaworski等人，Cell Mol Life Science[細胞與分子生命科學]2016.73,459-473)。 MALT1 (Mucous Membrane Associated Lymphoid Tissue Lymphoma Translocation 1) is a key mediator of the classical NFKB communication pathway. MALT1 is the only human paracaspase (paracaspase) and transduces signals from B cell receptor (BCR) and T cell receptor (TCR). MALT1 is the active subunit of the CBM complex formed after receptor activation. The CBM complex is composed of multiple subunits of three proteins: CARD11 (caspase recruitment domain family member 11), BCL10 (B cell CLL/lymphoma 10) And MALT1. MALT1 affects NFKB signaling through two mechanisms: first, MALT1 acts as a scaffold protein and recruits NFKB signaling proteins, such as TRAF6, TAB-TAK1, or NEMO-IKKα/β; second, MALT1, which is a cysteine protease, cleaves and is This inactivates the negative regulator of NFKB signaling, such as RelB, A20 or CYLD. The ultimate endpoint of MALT1 activity is the nuclear translocation of the FKB transcription factor complex and the activation of FKB signaling (Jaworski et al., Cell Mol Life Science [Cell and Molecular Life Science] 2016.73,459-473).

FKB傳訊的組成性激活係ABC-DLBCL(激活的B細胞樣亞型的彌漫性大B細胞淋巴瘤，其係DLBCL的更具攻擊性的形式)的標誌。DLBCL係非何杰金氏淋巴瘤(NHL)的最常見形式，大約占淋巴瘤病例的25%，而ABC-DLBCL大約占DLBCL的40%。在ABC-DLBCL患者中，NFKB途徑激活係由傳訊組分(例如，CD79A/B、CARD11、MYD88或A20)的突變驅動的(Staudt,Cold Spring Harb Perspect Biol[冷泉港生物學展望]2010,2；Lim等人，Immunol Rev[免疫學評論]2012,246,359-378)。 The constitutive activation of FKB signaling is a hallmark of ABC-DLBCL (activated B-cell-like subtype diffuse large B-cell lymphoma, which is a more aggressive form of DLBCL). DLBCL is the most common form of non-Hodgkin’s lymphoma (NHL) and accounts for approximately 25% of lymphoma cases, while ABC-DLBCL accounts for approximately 40% of DLBCL. In patients with ABC-DLBCL, the activation of the NFKB pathway is driven by mutations in the messaging component (for example, CD79A/B, CARD11, MYD88, or A20) (Staudt, Cold Spring Harb Perspect Biol [冷泉港生物 Prospect] 2010, 2 ; Lim et al., Immunol Rev [Immunology Review] 2012, 246, 359-378).

使用BTK抑制劑(例如依魯替尼(Ibrutinib))提供了在ABC-DLBCL中抑制NFKB傳訊有效的臨床概念證明。MALT1在NFKB傳訊途徑中BTK的下游，並且MALT1抑制劑可靶向對依魯替尼無反應的ABC-DLBCL患者(主要是具有CARD11突變的患者)，以及治療已獲得對依魯替尼的抗性的患者。 The use of BTK inhibitors (such as Ibrutinib) provides a clinical proof of concept effective in inhibiting NFKB communication in ABC-DLBCL. MALT1 is downstream of BTK in the NFKB signaling pathway, and MALT1 inhibitors can target ABC-DLBCL patients who do not respond to ibrutinib (mainly patients with CARD11 mutations), and treatment has acquired resistance to ibrutinib Sexual patients.

MALT1蛋白酶的小分子工具化合物抑制劑已在ABC-DLBCL的臨床前模型中表現出功效(Fontan等人，Cancer Cell[癌細胞]2012,22,812-824；Nagel等人，Cancer Cell[癌細胞]2012,22,825-837)。有趣的是，已經描述了MALT1蛋白酶功能的共價催化位點和變構抑制劑，這表明該蛋白酶的抑制劑可用作藥劑(Demeyer等人，Trends Mol Med[分子醫學趨勢]2016,22,135-150)。 Small molecule tool compound inhibitors of MALT1 protease have shown efficacy in preclinical models of ABC-DLBCL (Fontan et al., Cancer Cell [cancer] 2012, 22, 812-824; Nagel et al., Cancer Cell [cancer] 2012 ,22,825-837). Interestingly, the covalent catalytic sites and allosteric inhibitors of the MALT1 protease function have been described, which indicates that inhibitors of the protease can be used as medicaments (Demeyer et al., Trends Mol Med [Molecular Medicine Trends] 2016, 22, 135- 150).

產生API2-MALT1融合癌蛋白的染色體易位係在MALT(黏膜相關淋巴組織)淋巴瘤中鑒定的最常見的突變。API2-MALT1係NFKB途徑的有效 活化劑(Rosebeck等人，World J Biol Chem[世界生物化學雜誌]2016,7,128-137)。 The chromosomal translocation that produces the API2-MALT1 fusion oncoprotein is the most common mutation identified in MALT (mucosa associated lymphoid tissue) lymphoma. API2-MALT1 is effective in NFKB pathway Activator (Rosebeck et al., World J Biol Chem [World Journal of Biological Chemistry] 2016, 7, 128-137).

API2-MALT1模擬配位基 API2-MALT1 analog ligand

結合的TNF受體，促進RIP1(其充當用於激活經典NFKB傳訊的支架)的TRAF2依賴性泛素化。此外，已顯示API2-MALT1切割並生成NFKB誘導激酶(NIK)的穩定的組成型活性片段，從而激活非經典FKB途徑(Rosebeck等人，Science[科學]，2011,331,468-472)。 The bound TNF receptor promotes TRAF2-dependent ubiquitination of RIP1, which acts as a scaffold for activating classical NFKB signaling. In addition, API2-MALT1 has been shown to cleave and generate stable constitutively active fragments of NFKB-inducible kinase (NIK), thereby activating the non-classical FKB pathway (Rosebeck et al., Science [Science], 2011, 331, 468-472).

除淋巴瘤外，已顯示MALT1在先天性和適應性免疫中起關鍵作用(Jaworski M等人，Cell Mol Life Sci.[細胞與分子生命科學]2016)。MALT1蛋白酶抑制劑可減輕小鼠實驗性變應性腦脊髓炎(多發性硬化症的小鼠模型)的疾病發作和進展(Mc Guire等人，J.Neuroinflammation[神經炎症雜誌]2014,11,124)。表現催化性失活的MALT1突變體的小鼠顯示出邊緣區B細胞和B1B細胞的缺失，以及以T和B細胞激活和增殖減少為特徵的一般免疫缺陷。然而，那些小鼠在9至10週齡時也會發生自發性多器官自體免疫炎症。仍知之甚少的是，為什麼失效MALT1蛋白酶敲入型小鼠顯示出耐受性的破壞，而常規MALT1 KO小鼠卻沒有顯示。一種假設表明，失效MALT1蛋白酶敲入型小鼠的免疫穩態失衡可能是由於T細胞和B細胞的不完全缺乏，但免疫調節細胞的嚴重缺乏引起的(Jaworski等人，EMBO J.[歐洲分子生物學學會雜誌]2014；Gewies等人，Cell Reports[細胞報告]2014；Bornancin等人，J.Immunology[免疫學雜誌]2015；Yu等人，PLOS One[公共科學圖書館期刊]2015)。類似地，人類MALT缺乏症與聯合免疫缺陷障礙有關(McKinnon等人，J.Allergy Clin.Immunol.[變態反應與臨床免疫學雜誌]2014,133,1458-1462；Jabara等人，J.Allergy Clin.Immunol.[變態反應與臨床免疫學雜誌]2013,132,151-158；Punwani等人，J.Clin.Immunol.[臨床免疫學雜誌]2015,35,135-146)。鑒於基因突變和藥理學抑制之間的差異，失效MALT1蛋白酶敲入型小鼠的表型可能與用MALT1蛋白酶抑制劑治療的患者的 表型不相似。藉由MALT1蛋白酶抑制來減少免疫抑制性T細胞可能藉由潛在地提高抗腫瘤免疫力而對癌症患者有益。 In addition to lymphoma, MALT1 has been shown to play a key role in innate and adaptive immunity (Jaworski M et al., Cell Mol Life Sci. [Cell and Molecular Life Sciences] 2016). MALT1 protease inhibitors can reduce the onset and progression of experimental allergic encephalomyelitis (a mouse model of multiple sclerosis) in mice (Mc Guire et al., J. Neuroinflammation [Journal of Neuroinflammation] 2014, 11, 124). Mice exhibiting a catalytically inactive MALT1 mutant showed a loss of B cells and B1B cells in the marginal zone, as well as general immunodeficiency characterized by reduced T and B cell activation and proliferation. However, those mice also developed spontaneous multi-organ autoimmune inflammation at 9 to 10 weeks of age. What is still poorly understood is why the disabled MALT1 protease knock-in mice showed a breakdown in tolerance, while the conventional MALT1 KO mice did not. A hypothesis suggests that the imbalance of immune homeostasis in mice with ineffective MALT1 protease knock-in mice may be caused by an incomplete lack of T cells and B cells, but a severe lack of immune regulatory cells (Jaworski et al., EMBO J. [European Molecules Journal of the Biological Society] 2014; Gewis et al., Cell Reports [cellular report] 2014; Bornancin et al., J.Immunology [Immunology Journal] 2015; Yu et al., PLOS One [Public Science Library Journal] 2015). Similarly, human MALT deficiency is associated with combined immunodeficiency disorder (McKinnon et al., J. Allergy Clin. Immunol. [Journal of Allergy and Clinical Immunology] 2014, 133, 1458-1462; Jabara et al., J. Allergy Clin .Immunol.[Journal of Allergy and Clinical Immunology]2013,132,151-158; Punwani et al., J.Clin.Immunol.[Journal of Clinical Immunology]2015,35,135-146). In view of the difference between gene mutation and pharmacological inhibition, the phenotype of ineffective MALT1 protease knock-in mice may be similar to that of patients treated with MALT1 protease inhibitors. The phenotypes are not similar. Reduction of immunosuppressive T cells by MALT1 protease inhibition may be beneficial to cancer patients by potentially improving anti-tumor immunity.

因此，MALT1抑制劑可為患有癌症和/或免疫性疾病的患者提供治療益處。 Therefore, MALT1 inhibitors can provide therapeutic benefits to patients suffering from cancer and/or immune diseases.

WO 2018/119036(其藉由引用併入本文)揭露了抑制MALT1的化合物，包括1-(1-側氧基-1,2-二氫異喹啉-5-基)-5-(三氟甲基)-N-[2-(三氟甲基)吡啶-4-基]-1H-吡唑-4-甲醯胺(WO 2018/119036中引用為化合物158)。 WO 2018/119036 (which is incorporated herein by reference) discloses compounds that inhibit MALT1, including 1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoro methyl) - N - [2- (trifluoromethyl) pyridin-4-yl] -1 H - pyrazole-4-acyl-amine (WO 2018/119036 cited compound 158).

需要提供1-(1-側氧基-1,2-二氫異喹啉-5-基)-5-(三氟甲基)-N-[2-(三氟甲基)吡啶-4-基]-1H-吡唑-4-甲醯胺的替代形式。 Need to provide 1-(1-side oxy-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl) -N -[2-(trifluoromethyl)pyridine-4- Alkyl]-1 H -pyrazole-4-carboxamide alternative form.

本發明關於1-(1-側氧基-1,2二氫異喹啉-5-基)-5-(三氟甲基)-N-(2-(三氟甲基)吡啶-4-基)-1H-吡唑-4-甲醯胺(化合物A)一水合物的結晶形式III： The present invention relates to 1-(1-oxo-1,2dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-N-(2-(trifluoromethyl)pyridine-4- Group)-1 H -pyrazole-4-carboxamide (Compound A) monohydrate crystal form III:

Figure 109105620-A0202-12-0004-1
Figure 109105620-A0202-12-0004-1

熟悉該項技術者將認識到，化合物A的其他互變異構排列係可能的。例如，應理解 Those familiar with the art will recognize that other tautomeric arrangements of compound A are possible. For example, it should be understood

Figure 109105620-A0202-12-0004-2
Figure 109105620-A0202-12-0004-2

能以另一種互變異構排列 Can be arranged in another tautomeric arrangement

Figure 109105620-A0202-12-0005-3
存在。
Figure 109105620-A0202-12-0005-3
exist.

在本發明的上下文中，在化合物A的結晶形式中，化合物A可以處於上述互變異構排列之一或者可以是其混合物，精確的互變異構排列係未知的。為了簡單起見，僅使用化合物A的基團的一種可能的互變異構排列來描述該等化合物，但是熟悉該項技術者應該清楚的是，在化合物A的結晶形式(例如化合物A一水合物的結晶形式III)中，化合物A可以處於上述互變異構排列之一或者可以是其混合物。 In the context of the present invention, in the crystalline form of Compound A, Compound A may be in one of the above-mentioned tautomeric arrangements or may be a mixture thereof, and the precise tautomeric arrangement is unknown. For the sake of simplicity, only one possible tautomeric arrangement of the groups of compound A is used to describe these compounds, but it should be clear to those skilled in the art that in the crystalline form of compound A (such as compound A monohydrate In the crystalline form III), Compound A may be in one of the above-mentioned tautomeric arrangements or may be a mixture thereof.

本發明的一個實施方式關於一種藥物組成物，該藥物組成物包含化合物A一水合物的結晶形式III。 One embodiment of the present invention relates to a pharmaceutical composition comprising crystalline form III of Compound A monohydrate.

本發明還提供了一種藥物組成物，該藥物組成物包含藥學上可接受的載體、藥學上可接受的賦形劑、和/或藥學上可接受的稀釋劑、以及化合物A一水合物的結晶形式III，由其組成和/或基本上由其組成。 The present invention also provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier, a pharmaceutically acceptable excipient, and/or a pharmaceutically acceptable diluent, and a crystal of Compound A monohydrate Form III consists of and/or consists essentially of it.

還提供了用於製備藥物組成物的方法，該等方法包括將化合物A一水合物的結晶形式III、以及藥學上可接受的載體、藥學上可接受的賦形劑、和/或藥學上可接受的稀釋劑混合，由其組成和/或基本上由其組成。 A method for preparing a pharmaceutical composition is also provided, which method comprises combining the crystalline form III of Compound A monohydrate, and a pharmaceutically acceptable carrier, a pharmaceutically acceptable excipient, and/or a pharmaceutically acceptable The accepted diluent mixes, consists of and/or consists essentially of it.

本發明進一步提供了使用化合物A一水合物的結晶形式III來治療或改善受試者(包括哺乳動物和/或人類)的疾病、綜合症、病症或障礙之方法，其中該疾病、綜合症、病症或障礙(包括但不限於癌症和/或免疫性疾病)受MALT1的抑制的影響。 The present invention further provides a method of using the crystalline form III of Compound A monohydrate to treat or ameliorate a disease, syndrome, disorder or disorder in a subject (including mammals and/or humans), wherein the disease, syndrome, Conditions or disorders (including but not limited to cancer and/or immune diseases) are affected by the inhibition of MALT1.

本發明還關於化合物A一水合物的結晶形式III在製備藥物中之用途，其中該藥物被製備用於治療受MALT1的抑制的影響的疾病、綜合症、障礙或病症，例如癌症和/或免疫性疾病。 The present invention also relates to the use of the crystalline form III of Compound A monohydrate in the preparation of medicaments, wherein the medicament is prepared for the treatment of diseases, syndromes, disorders or conditions affected by the inhibition of MALT1, such as cancer and/or immunity Sexual disease.

本發明例示了治療由MALT1介導的疾病、綜合症、病症或障礙的方法，該疾病、綜合症、病症或障礙選自由以下項組成之群組：淋巴瘤，白血病，癌和肉瘤，例如非何杰金氏淋巴瘤(NHL)、B細胞NHL、彌漫性大B細胞淋巴瘤(DLBCL)、外膜細胞淋巴瘤(MCL)、濾泡性淋巴瘤(FL)、黏膜相關淋巴組織(MALT)淋巴瘤、邊緣區淋巴瘤、T細胞淋巴瘤、何杰金氏淋巴瘤、柏基特氏淋巴瘤、多發性骨髓瘤、慢性淋巴細胞性白血病(CLL)、小淋巴細胞淋巴瘤(SLL)、瓦爾登斯特倫巨球蛋白血症、淋巴母細胞T細胞白血病、慢性髓細胞性白血病(CML)、毛細胞白血病、急性淋巴母細胞T細胞白血病、漿細胞瘤、免疫母細胞性大細胞白血病、巨核母細胞性白血病、急性巨核細胞白血病、前髓細胞白血病、紅白血病、腦癌(神經膠質瘤)、惡性膠質瘤、乳腺癌、結腸直腸癌/結腸癌、***癌、肺癌(包括非小細胞肺癌)、胃癌、子宮內膜癌、黑素瘤、胰臟癌、肝癌、腎癌(kidney cancer)、鱗狀細胞癌、卵巢癌、肉瘤、骨肉瘤、甲狀腺癌、膀胱癌、頭頸癌、睾丸癌、尤因氏肉瘤、橫紋肌肉瘤、成神經管細胞瘤、神經母細胞瘤、子宮頸癌、腎癌(renal cancer)、尿路上皮癌、外陰癌、食管癌、唾液腺癌、鼻咽癌、頰癌、口腔癌、以及GIST(胃腸道間質瘤)，該等方法包括向有需要的受試者投與治療有效量的化合物A一水合物的結晶形式III，由其組成和/或基本上由其組成。 The present invention exemplifies a method for treating diseases, syndromes, disorders or disorders mediated by MALT1, the disease, syndrome, disorder or disorder selected from the group consisting of: lymphoma, leukemia, cancer and sarcoma, such as non Hodgkin’s lymphoma (NHL), B-cell NHL, diffuse large B-cell lymphoma (DLBCL), adventitia cell lymphoma (MCL), follicular lymphoma (FL), mucosa-associated lymphoid tissue (MALT) Lymphoma, marginal zone lymphoma, T cell lymphoma, Hodgkin’s lymphoma, Burkitt’s lymphoma, multiple myeloma, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), Waldenstrom's macroglobulinemia, lymphoblastic T cell leukemia, chronic myeloid leukemia (CML), hairy cell leukemia, acute lymphoblastic T cell leukemia, plasmacytoma, immunoblastic large cell leukemia , Megakaryoblastic leukemia, acute megakaryocyte leukemia, promyelocytic leukemia, erythroleukemia, brain cancer (glioma), malignant glioma, breast cancer, colorectal cancer/colon cancer, prostate cancer, lung cancer (including non-small Cell lung cancer), stomach cancer, endometrial cancer, melanoma, pancreatic cancer, liver cancer, kidney cancer (kidney cancer), squamous cell carcinoma, ovarian cancer, sarcoma, osteosarcoma, thyroid cancer, bladder cancer, head and neck cancer, Testicular cancer, Ewing's sarcoma, rhabdomyosarcoma, medulloblastoma, neuroblastoma, cervical cancer, renal cancer, urothelial cancer, vulvar cancer, esophageal cancer, salivary gland cancer, nasopharyngeal cancer , Buccal cancer, oral cancer, and GIST (gastrointestinal stromal tumor), these methods include administering to a subject in need a therapeutically effective amount of compound A monohydrate crystal form III, which consists of and/or Basically consists of it.

在另一個實施方式中，本發明關於化合物A一水合物的結晶形式III，其用於作為藥物使用。 In another embodiment, the present invention relates to the crystalline form III of Compound A monohydrate, which is used as a medicine.

在另一個實施方式中，本發明關於化合物A一水合物的結晶形式III，其用於在治療受MALT1的抑制的影響的疾病、綜合症、病症或障礙中使用，該疾病、綜合症、病症或障礙選自由以下項組成之群組：淋巴瘤，白血病，癌和肉瘤，例如非何杰金氏淋巴瘤(NHL)、B細胞NHL、彌漫性大B細胞淋巴瘤(DLBCL)、外膜細胞淋巴瘤(MCL)、濾泡性淋巴瘤(FL)、黏膜相關淋巴組織(MALT)淋巴瘤、邊緣區淋巴瘤、T細胞淋巴瘤、何杰金氏淋巴瘤、柏基 特氏淋巴瘤、多發性骨髓瘤、慢性淋巴細胞性白血病(CLL)、小淋巴細胞淋巴瘤(SLL)、瓦爾登斯特倫巨球蛋白血症、淋巴母細胞T細胞白血病、慢性髓細胞性白血病(CML)、毛細胞白血病、急性淋巴母細胞T細胞白血病、漿細胞瘤、免疫母細胞性大細胞白血病、巨核母細胞性白血病、急性巨核細胞白血病、前髓細胞白血病、紅白血病、腦癌(神經膠質瘤)、惡性膠質瘤、乳腺癌、結腸直腸癌/結腸癌、***癌、肺癌(包括非小細胞肺癌)、胃癌、子宮內膜癌、黑素瘤、胰臟癌、肝癌、腎癌(kidney cancer)、鱗狀細胞癌、卵巢癌、肉瘤、骨肉瘤、甲狀腺癌、膀胱癌、頭頸癌、睾丸癌、尤因氏肉瘤、橫紋肌肉瘤、成神經管細胞瘤、神經母細胞瘤、子宮頸癌、腎癌(renal cancer)、尿路上皮癌、外陰癌、食管癌、唾液腺癌、鼻咽癌、頰癌、口腔癌、以及GIST(胃腸道間質瘤)。 In another embodiment, the present invention relates to the crystalline form III of compound A monohydrate for use in the treatment of diseases, syndromes, disorders or disorders affected by the inhibition of MALT1, such diseases, syndromes, disorders Or disorder is selected from the group consisting of: lymphoma, leukemia, carcinoma and sarcoma, such as non-Hodgkin’s lymphoma (NHL), B-cell NHL, diffuse large B-cell lymphoma (DLBCL), adventitia cells Lymphoma (MCL), follicular lymphoma (FL), mucosa-associated lymphoid tissue (MALT) lymphoma, marginal zone lymphoma, T cell lymphoma, Hodgkin’s lymphoma, Burke Tert's lymphoma, multiple myeloma, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), Waldenstrom's macroglobulinemia, lymphoblastic T-cell leukemia, chronic myelogenous Leukemia (CML), hairy cell leukemia, acute lymphoblastic T-cell leukemia, plasmacytoma, immunoblastic large cell leukemia, megakaryocyte leukemia, acute megakaryocyte leukemia, promyelocytic leukemia, erythroleukemia, brain cancer (Glioma), malignant glioma, breast cancer, colorectal cancer/colon cancer, prostate cancer, lung cancer (including non-small cell lung cancer), gastric cancer, endometrial cancer, melanoma, pancreatic cancer, liver cancer, kidney Cancer (kidney cancer), squamous cell carcinoma, ovarian cancer, sarcoma, osteosarcoma, thyroid cancer, bladder cancer, head and neck cancer, testicular cancer, Ewing's sarcoma, rhabdomyosarcoma, medulloblastoma, neuroblastoma, Cervical cancer, renal cancer, urothelial cancer, vulvar cancer, esophageal cancer, salivary gland cancer, nasopharyngeal cancer, buccal cancer, oral cancer, and GIST (gastrointestinal stromal tumor).

在另一個實施方式中，本發明關於包含化合物A一水合物的結晶形式III的組成物，該組成物用於治療受MALT1的抑制的影響的疾病、綜合症、病症或障礙，該疾病、綜合症、病症或障礙選自由以下項組成之群組：淋巴瘤，白血病，癌和肉瘤，例如非何杰金氏淋巴瘤(NHL)、B細胞NHL、彌漫性大B細胞淋巴瘤(DLBCL)、外膜細胞淋巴瘤(MCL)、濾泡性淋巴瘤(FL)、黏膜相關淋巴組織(MALT)淋巴瘤、邊緣區淋巴瘤、T細胞淋巴瘤、何杰金氏淋巴瘤、柏基特氏淋巴瘤、多發性骨髓瘤、慢性淋巴細胞性白血病(CLL)、小淋巴細胞淋巴瘤(SLL)、瓦爾登斯特倫巨球蛋白血症、淋巴母細胞T細胞白血病、慢性髓細胞性白血病(CML)、毛細胞白血病、急性淋巴母細胞T細胞白血病、漿細胞瘤、免疫母細胞性大細胞白血病、巨核母細胞性白血病、急性巨核細胞白血病、前髓細胞白血病、紅白血病、腦癌(神經膠質瘤)、惡性膠質瘤、乳腺癌、結腸直腸癌/結腸癌、***癌、肺癌(包括非小細胞肺癌)、胃癌、子宮內膜癌、黑素瘤、胰臟癌、肝癌、腎癌(kidney cancer)、鱗狀細胞癌、卵巢癌、肉瘤、骨肉瘤、甲狀腺癌、膀胱癌、頭頸癌、睾丸癌、尤因氏肉瘤、橫紋 肌肉瘤、成神經管細胞瘤、神經母細胞瘤、子宮頸癌、腎癌(renal cancer)、尿路上皮癌、外陰癌、食管癌、唾液腺癌、鼻咽癌、頰癌、口腔癌、以及GIST(胃腸道間質瘤)。 In another embodiment, the present invention relates to a composition comprising the crystalline form III of Compound A monohydrate for the treatment of diseases, syndromes, disorders, or disorders affected by the inhibition of MALT1, such diseases, complexes The disease, disorder or disorder is selected from the group consisting of: lymphoma, leukemia, cancer and sarcoma, such as non-Hodgkin’s lymphoma (NHL), B-cell NHL, diffuse large B-cell lymphoma (DLBCL), Outer membrane cell lymphoma (MCL), follicular lymphoma (FL), mucosa-associated lymphoid tissue (MALT) lymphoma, marginal zone lymphoma, T-cell lymphoma, Hodgkin’s lymphoma, Burkitt’s lymphoma Tumor, multiple myeloma, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), Waldenstrom macroglobulinemia, lymphoblastic T-cell leukemia, chronic myelogenous leukemia (CML) ), hairy cell leukemia, acute lymphoblastic T cell leukemia, plasmacytoma, immunoblastic large cell leukemia, megakaryoblastic leukemia, acute megakaryocyte leukemia, promyelocytic leukemia, erythroleukemia, brain cancer (glial Tumor), malignant glioma, breast cancer, colorectal cancer/colon cancer, prostate cancer, lung cancer (including non-small cell lung cancer), stomach cancer, endometrial cancer, melanoma, pancreatic cancer, liver cancer, kidney cancer (kidney cancer), squamous cell carcinoma, ovarian cancer, sarcoma, osteosarcoma, thyroid cancer, bladder cancer, head and neck cancer, testicular cancer, Ewing's sarcoma, rhabdomen Sarcoma, medulloblastoma, neuroblastoma, cervical cancer, renal cancer, urothelial cancer, vulvar cancer, esophageal cancer, salivary gland cancer, nasopharyngeal cancer, buccal cancer, oral cancer, and GIST (Gastrointestinal Stromal Tumor).

在另一個實施方式中，本發明關於包含化合物A一水合物的結晶形式III的組成物，該組成物用於治療受MALT1的抑制的影響的疾病、綜合症、病症或障礙，該疾病、綜合症、病症或障礙選自由以下項組成之群組：彌漫性大B細胞淋巴瘤(DLBCL)、外膜細胞淋巴瘤(MCL)、濾泡性淋巴瘤(FL)、以及黏膜相關淋巴組織(MALT)淋巴瘤。 In another embodiment, the present invention relates to a composition comprising the crystalline form III of Compound A monohydrate for the treatment of diseases, syndromes, disorders, or disorders affected by the inhibition of MALT1, such diseases, complexes The disease, disorder, or disorder is selected from the group consisting of: diffuse large B-cell lymphoma (DLBCL), adventitia cell lymphoma (MCL), follicular lymphoma (FL), and mucosa-associated lymphoid tissue (MALT) ) Lymphoma.

本發明的一個實施方式關於包含化合物A一水合物的結晶形式III的組成物，該組成物用於治療受MALT1的抑制的影響的免疫性疾病，該等免疫性疾病包括但不限於自體免疫障礙和炎性障礙，例如關節炎、炎症性腸病、胃炎、強直性脊柱炎、潰瘍性結腸炎、胰腺炎、克羅恩氏病、乳糜瀉、多發性硬化症、全身性紅斑狼瘡、狼瘡性腎炎、風濕熱、痛風、器官或移植排斥、慢性同種異體移植排斥、急性或慢性移植物抗宿主病、皮炎(包括特應性皮炎、皮肌炎、牛皮癬)、貝赫切特氏病(Behcet's diseases)、眼色素層炎、重症肌無力、格雷夫斯病、橋本甲狀腺炎、乾燥綜合症、起泡障礙、抗體介導的血管炎綜合症、免疫複合物血管炎、過敏障礙、氣喘、支氣管炎、慢性阻塞性肺病(COPD)、囊性纖維化、肺炎、肺部疾病(包括水腫、栓塞)、纖維化、類肉瘤病、高血壓和肺氣腫、矽肺、呼吸衰竭、急性呼吸窘迫症候群、BENTA疾病、鈹中毒、以及多肌炎。 One embodiment of the present invention relates to a composition comprising the crystalline form III of Compound A monohydrate, which is used for the treatment of immune diseases affected by the inhibition of MALT1, such immune diseases including but not limited to autoimmunity Disorders and inflammatory disorders, such as arthritis, inflammatory bowel disease, gastritis, ankylosing spondylitis, ulcerative colitis, pancreatitis, Crohn’s disease, celiac disease, multiple sclerosis, systemic lupus erythematosus, lupus Nephritis, rheumatic fever, gout, organ or transplant rejection, chronic allograft rejection, acute or chronic graft-versus-host disease, dermatitis (including atopic dermatitis, dermatomyositis, psoriasis), Behçet’s disease ( Behcet's diseases), uveitis, myasthenia gravis, Graves' disease, Hashimoto’s thyroiditis, Sjogren’s syndrome, blistering disorders, antibody-mediated vasculitis syndrome, immune complex vasculitis, allergic disorders, asthma, Bronchitis, chronic obstructive pulmonary disease (COPD), cystic fibrosis, pneumonia, lung diseases (including edema, embolism), fibrosis, sarcoidosis, hypertension and emphysema, silicosis, respiratory failure, acute respiratory distress Syndrome, BENTA disease, beryllium poisoning, and polymyositis.

在另一個實施方式中，本發明關於包含化合物A一水合物的結晶形式III的組成物，該組成物用於治療受MALT1的抑制的影響的疾病、綜合症、病症或障礙，該疾病、綜合症、病症或障礙選自由以下項組成之群組：類風濕性關節炎(RA)、牛皮癬性關節炎(PsA)、牛皮癬(Pso)、潰瘍性結腸炎(UC)、克羅恩氏病、全身性紅斑狼瘡(SLE)、氣喘、以及慢性阻塞性肺病(COPD)。 In another embodiment, the present invention relates to a composition comprising the crystalline form III of Compound A monohydrate for the treatment of diseases, syndromes, disorders, or disorders affected by the inhibition of MALT1, such diseases, complexes Disease, disease or disorder selected from the group consisting of rheumatoid arthritis (RA), psoriatic arthritis (PsA), psoriasis (Pso), ulcerative colitis (UC), Crohn’s disease, Systemic lupus erythematosus (SLE), asthma, and chronic obstructive pulmonary disease (COPD).

本發明還關於化合物A一水合物的結晶形式III的製備。 The present invention also relates to the preparation of the crystalline form III of Compound A monohydrate.

當結合附圖閱讀時，將進一步理解本發明內容以及以下的具體實施方式。出於說明本發明的目的，在附圖中顯示出了本發明的示例性實施方式；然而，本發明並不限於該等附圖的特定揭露內容。在該等附圖中： When read in conjunction with the drawings, one will further understand the content of the present invention and the following specific embodiments. For the purpose of illustrating the present invention, exemplary embodiments of the present invention are shown in the accompanying drawings; however, the present invention is not limited to the specific disclosure of the accompanying drawings. In the drawings:

[圖1]係化合物A一水合物形式III之X射線粉末繞射圖(XRPD)模式。 [ Figure 1 ] X-ray powder diffraction pattern (XRPD) mode of compound A monohydrate form III.

[圖2]係化合物A一水合物形式III之差示掃描量熱法(DSC)熱譜圖。 [ Figure 2 ] Differential scanning calorimetry (DSC) thermogram of compound A monohydrate form III.

[圖3]係化合物A一水合物形式III之熱重量分析(TGA)曲線。 [ Figure 3 ] Thermogravimetric analysis (TGA) curve of compound A monohydrate form III.

[圖4]係化合物A一水合物形式III之動態蒸汽吸附(DVS)等溫線圖。 [ Figure 4 ] is the dynamic vapor adsorption (DVS) isotherm diagram of compound A monohydrate form III.

[圖5]係化合物A一水合物形式III之DVS質量變化圖。 [ Figure 5 ] DVS mass change diagram of compound A monohydrate form III.

[圖6]係化合物A一水合物形式III之紅外(IR)光譜。 [ Figure 6 ] The infrared (IR) spectrum of Compound A monohydrate Form III.

[圖7]係化合物A水合物形式I之XRPD圖。 [ Figure 7 ] XRPD pattern of Compound A Hydrate Form I.

[圖8]係化合物A水合物形式I之DSC熱譜圖。 [ Figure 8 ] DSC thermogram of Compound A Hydrate Form I.

[圖9]係化合物A水合物形式I之TGA曲線。 [ Figure 9 ] The TGA curve of Compound A Hydrate Form I.

[圖10]係化合物A水合物形式I之DVS等溫線圖。 [ Figure 10 ] DVS isotherm diagram of Compound A Hydrate Form I.

[圖11]係化合物A水合物形式I之DVS質量變化圖。 [ Figure 11 ] DVS mass change graph of Compound A Hydrate Form I.

[圖12]係化合物A水合物形式I之IR光譜。 [ Figure 12 ] The IR spectrum of Compound A Hydrate Form I.

本揭露可以藉由參考以下描述更充分地理解，包括以下術語詞彙表和總結性實例。應理解，為了清楚起見，在單獨的方面的上下文中本文描述 的所揭露的結晶形式、組成物和方法的某些特徵也可以在單個方面中以組合來提供。相反，為了簡潔起見，在單個方面的上下文中描述的所揭露的結晶形式、組成物和方法的不同特徵也可以單獨提供或以任何亞組合提供。 This disclosure can be more fully understood by referring to the following description, including the following glossary of terms and summary examples. It should be understood that, for the sake of clarity, this text is described in the context of a separate aspect Certain features of the disclosed crystalline forms, compositions, and methods of can also be provided in combination in a single aspect. On the contrary, for the sake of brevity, the different features of the disclosed crystalline forms, compositions, and methods described in the context of a single aspect may also be provided separately or in any sub-combination.

本文給出的一些定量表現沒有用術語「約」限定。應理解，無論是否明確地使用術語「約」，本文給出的每個量意指實際給出的值，並且還意指基於熟悉該項技術者合理推斷的此類給定值的近似值，包括由於針對此類給定值的實驗和/或測量條件導致的近似值。 Some quantitative performances given in this article are not limited by the term "about". It should be understood that, regardless of whether the term "about" is used explicitly or not, each quantity given herein means the actual value given, and also means an approximate value based on such given value reasonably inferred by those skilled in the art, including Approximate values due to experimental and/or measurement conditions for such given values.

在本申請的整個說明書和申請專利範圍中，詞語「包含 (comprise)」和「含有(contain)」，以及該等詞的變形例如「包含(comprising和comprises)」意指「包括但不限於」且不意欲(並且不)排除其他組分。 In the entire specification of this application and the scope of the patent application, the phrase "including (comprise)" and "contain", and variations of these words such as "comprising (comprising and comprises)" means "including but not limited to" and are not intended to (and not) exclude other components.

出於本揭露的目的，術語「結晶形式」和「多晶型物」係同義詞。本文提供了結晶形式的表徵資訊。應理解，可以使用熟悉該項技術者將認識到的足以建立具體形式的存在的表徵資訊的任何部分來實現具體形式的確定。例如，即使係單個區分峰也足以使熟悉該項技術者理解存在具體形式。 For the purpose of this disclosure, the terms "crystalline form" and "polymorph" are synonymous. This article provides information on the characterization of the crystalline form. It should be understood that any part of the characterizing information that is sufficient to establish the existence of the specific form that those skilled in the art will recognize can be used to achieve the determination of the specific form. For example, even a single distinguishing peak is sufficient for those skilled in the art to understand that there are specific forms.

術語「分離形式」係指以與另外一種或多種化合物的任何混合物、溶劑系統或生物環境分開的形式存在的化合物。在本發明的一個實施方式中，該結晶形式以分離形式存在。 The term "isolated form" refers to a compound that exists in a form separate from any mixture, solvent system, or biological environment of another compound or compounds. In one embodiment of the present invention, the crystalline form exists in an isolated form.

術語「室溫(RT)」係指從約15℃至約30℃，具體是從約20℃至約30℃的溫度。較佳的是，室溫係約25℃的溫度。 The term "room temperature (RT)" refers to a temperature from about 15°C to about 30°C, specifically from about 20°C to about 30°C. Preferably, the room temperature is about 25°C.

當使用一個或多個以角度2θ(2 theta)給出的XRPD峰鑒定結晶形式時，除非另有說明，否則每個2θ值均應理解為意指給定值±0.2°。 When one or more XRPD peaks given at an angle 2 theta (2 theta) are used to identify a crystalline form, unless otherwise specified, each 2 theta value should be understood to mean a given value ±0.2°.

當使用來自差示掃描量熱法熱譜圖(DSC)曲線的一個或多個溫度(例如，吸熱轉變開始、熔融等)鑒定結晶形式時，除非另有說明，否則每個溫度值均應理解為意指給定值±2℃。 When using one or more temperatures from a differential scanning calorimetry (DSC) curve (for example, endothermic transition start, melting, etc.) to identify a crystalline form, unless otherwise specified, each temperature value should be understood It means the given value ± 2°C.

術語「晶種接種」係指將結晶材料添加至溶液或混合物中以引發結晶或重結晶。 The term "seed seeding" refers to the addition of crystalline material to a solution or mixture to initiate crystallization or recrystallization.

化合物A能以溶劑化物存在。「溶劑化物」可以是與水(即水合物)或與普通有機溶劑的溶劑化物。 Compound A can exist as a solvate. The "solvate" can be a solvate with water (ie, a hydrate) or a common organic solvent.

化合物A一水合物的結晶形式III能以基本上純的形式提供，其中呈分離的結晶形式的雜質的莫耳百分比小於約5莫耳百分比，較佳的是小於約2莫耳百分比，更較佳的是小於約0.5莫耳百分比，最較佳的是小於約0.1莫耳百分比。在本發明的一個實施方式中，化合物A一水合物的結晶形式III以基本上純的形式存在。 The crystalline form III of Compound A monohydrate can be provided in a substantially pure form, wherein the molar percentage of impurities in the isolated crystalline form is less than about 5 molar percent, preferably less than about 2 molar percent, and more It is preferably less than about 0.5 mol%, and most preferably less than about 0.1 mol%. In one embodiment of the invention, the crystalline form III of Compound A monohydrate exists in a substantially pure form.

本文還提供了化合物A，作為化合物A一水合物的結晶形式III與化合物A或其溶劑化物的一種或多種另外的形式的混合物。至少具體重量百分比的化合物A可以是化合物A一水合物的結晶形式III。具體重量百分比包括10%、20%、30%、40%、50%、60%、70%、80%、85%、90%、95%、96%、97%、98%、99%、99.5%和99.9%。當具體重量百分比的化合物係一水合物結晶形式III時，化合物的其餘部分可以是化合物A的無定形形式、化合物A水合物結晶形式I、化合物A的一種或多種其他結晶形式、或其混合物。 Also provided herein is Compound A as a mixture of crystalline form III of Compound A monohydrate and one or more additional forms of Compound A or a solvate thereof. At least a specific weight percentage of Compound A may be the crystalline form III of Compound A monohydrate. Specific weight percentages include 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5 % And 99.9%. When the specific weight percentage of the compound is monohydrate crystalline form III, the remaining part of the compound may be the amorphous form of compound A, the crystalline form I of compound A hydrate, one or more other crystalline forms of compound A, or a mixture thereof.

「藥學上可接受的」意指由聯邦或州政府的監管機構或美國以外的國家的相應機構批准的或可批准的，或者美國藥典中或其他公認藥典中列出的在動物(更特別地，在人類中)中使用的。 "Pharmaceutically acceptable" means approved or approvable by a regulatory agency of the federal or state government or a corresponding agency in a country other than the United States, or listed in the United States Pharmacopoeia or other recognized pharmacopoeia in animals (more particularly , Used in humans).

術語「受試者」係指已係治療、觀察或實驗對象的動物，較佳的是哺乳動物，最較佳的是人類。 The term "subject" refers to an animal that has been a subject of treatment, observation, or experiment, preferably a mammal, and most preferably a human.

術語「治療有效量」係指活性化合物或藥劑(包括本發明的結晶形式)的量，該量引起研究人員、獸醫、醫師或其他臨床醫生所尋求的在組織系統、動物或人類中的生物學或醫學應答，包括減少或抑制酶或蛋白質活性、或改善症狀、緩解病症、減慢或延緩疾病進展、或預防疾病。 The term "therapeutically effective amount" refers to the amount of the active compound or agent (including the crystalline form of the present invention) that causes the biology in tissue systems, animals or humans sought by researchers, veterinarians, physicians, or other clinicians. Or medical response, including reducing or inhibiting enzyme or protein activity, or improving symptoms, alleviating symptoms, slowing down or delaying disease progression, or preventing disease.

在一個實施方式中，術語「治療有效量」係指當投與至受試者時能夠在下列方面起效的本發明的結晶形式的量：(1)至少部分緩解、抑制、防止和/或減輕(i)由MALT1介導的；或(ii)與MALT1活性相關的；或(iii)以MALT1的(正常或異常)活性為特徵的障礙或疾病；或者(2)降低或抑制MALT1的活性；或者(3)降低或抑制MALT1的表現；或者(4)修飾MALT1的蛋白質水平。 In one embodiment, the term "therapeutically effective amount" refers to the amount of the crystalline form of the present invention that when administered to a subject is effective in the following aspects: (1) at least partially alleviate, inhibit, prevent and/or Alleviate (i) mediated by MALT1; or (ii) related to MALT1 activity; or (iii) disorders or diseases characterized by the (normal or abnormal) activity of MALT1; or (2) reduce or inhibit MALT1 activity ; Or (3) reduce or inhibit the performance of MALT1; or (4) modify the protein level of MALT1.

術語「組成物」係指包括治療有效量的指定成分的產品，以及任何直接或間接由指定量的指定成分的組合產生的產品。 The term "composition" refers to a product that includes a therapeutically effective amount of specified ingredients, and any product that is directly or indirectly produced from a combination of specified amounts of specified ingredients.

術語「MALT1介導的」係指在沒有MALT1的情況下可能發生但在存在MALT1的情況下可發生的任何疾病、綜合症、病症或障礙。由MALT1介導的疾病、綜合症、病症或障礙的合適實例包括但不限於淋巴瘤，白血病，癌和肉瘤，例如非何杰金氏淋巴瘤(NHL)、B細胞NHL、彌漫性大B細胞淋巴瘤(DLBCL)、外膜細胞淋巴瘤(MCL)、濾泡性淋巴瘤(FL)、黏膜相關淋巴組織(MALT)淋巴瘤、邊緣區淋巴瘤、T細胞淋巴瘤、何杰金氏淋巴瘤、柏基特氏淋巴瘤、多發性骨髓瘤、慢性淋巴細胞性白血病(CLL)、小淋巴細胞淋巴瘤(SLL)、瓦爾登斯特倫巨球蛋白血症、淋巴母細胞T細胞白血病、慢性髓細胞性白血病(CML)、毛細胞白血病、急性淋巴母細胞T細胞白血病、漿細胞瘤、免疫母細胞性大細胞白血病、巨核母細胞性白血病、急性巨核細胞白血病、前髓細胞白血病、紅白血病、腦癌(神經膠質瘤)、惡性膠質瘤、乳腺癌、結腸直腸癌/結腸癌、***癌、肺癌(包括非小細胞肺癌)、胃癌、子宮內膜癌、黑素瘤、胰臟癌、肝癌、腎癌(kidney cancer)、鱗狀細胞癌、卵巢癌、肉瘤、骨肉瘤、甲狀腺癌、膀胱癌、頭頸癌、睾丸癌、尤因氏肉瘤、橫紋肌肉瘤、成神經管細胞瘤、神經母細胞瘤、子宮頸癌、腎癌(renal cancer)、尿路上皮癌、外陰癌、食管癌、唾液腺癌、鼻咽癌、頰癌、口腔癌、以及GIST(胃腸道間質瘤)。 The term "MALT1-mediated" refers to any disease, syndrome, disorder or disorder that can occur in the absence of MALT1 but can occur in the presence of MALT1. Suitable examples of diseases, syndromes, disorders or disorders mediated by MALT1 include, but are not limited to, lymphoma, leukemia, cancer and sarcoma, such as non-Hodgkin’s lymphoma (NHL), B-cell NHL, diffuse large B-cell Lymphoma (DLBCL), adventitia cell lymphoma (MCL), follicular lymphoma (FL), mucosa-associated lymphoid tissue (MALT) lymphoma, marginal zone lymphoma, T cell lymphoma, Hodgkin’s lymphoma , Burkitt’s lymphoma, multiple myeloma, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), Waldenstrom's macroglobulinemia, lymphoblastic T-cell leukemia, chronic Myeloid leukemia (CML), hairy cell leukemia, acute lymphoblastic T cell leukemia, plasmacytoma, immunoblastic large cell leukemia, megakaryocyte leukemia, acute megakaryocyte leukemia, promyelocytic leukemia, erythroleukemia , Brain cancer (glioma), malignant glioma, breast cancer, colorectal cancer/colon cancer, prostate cancer, lung cancer (including non-small cell lung cancer), stomach cancer, endometrial cancer, melanoma, pancreatic cancer, Liver cancer, kidney cancer (kidney cancer), squamous cell carcinoma, ovarian cancer, sarcoma, osteosarcoma, thyroid cancer, bladder cancer, head and neck cancer, testicular cancer, Ewing's sarcoma, rhabdomyosarcoma, medulloblastoma, neuroblastoma Cell tumor, cervical cancer, renal cancer, urothelial cancer, vulvar cancer, esophageal cancer, salivary gland cancer, nasopharyngeal cancer, buccal cancer, oral cavity cancer, and GIST (gastrointestinal stromal tumor).

如本文所用，術語「MALT1抑制劑」係指抑制或減少MALT1的至少一種病症、症狀、障礙和/或疾病的藥劑。 As used herein, the term "MALT1 inhibitor" refers to an agent that inhibits or reduces at least one condition, symptom, disorder, and/or disease of MALT1.

如本文所用，除非另有說明，否則術語「影響(affect)」或「受影響(affected)」(當指的是受MALT1的抑制的影響的疾病、綜合症、病症或障礙時)包括所述疾病、綜合症、病症或障礙的一種或多種症狀或表現的頻率和/或嚴重性的降低；和/或包括預防所述疾病、綜合症、病症或障礙的一種或多種症狀或表現的發展或者該疾病、病症、綜合症或障礙的發展。 As used herein, unless otherwise stated, the term "affected" or "affected" (when referring to a disease, syndrome, disorder, or disorder affected by the inhibition of MALT1) includes the A reduction in the frequency and/or severity of one or more symptoms or manifestations of a disease, syndrome, disorder, or disorder; and/or includes preventing the development of one or more symptoms or manifestations of the disease, syndrome, disorder, or disorder; The development of the disease, condition, syndrome or disorder.

如本文所用，在一個實施方式中，術語任何疾病、病症、綜合症或障礙的「治療(treat、treating或treatment)」係指改善該疾病、病症、綜合症或障礙(即，減慢或阻止或減少該疾病或其至少一種臨床症狀的發展)。在另一個實施方式中，「治療(treat、treating或treatment)」係指緩解或改善至少一種身體參數，包括不能被患者辨別的那些。在另外的實施方式中，「治療(treat、treating或treatment)」係指在身體方面(例如可辨別的症狀的穩定)、生理學方面(例如身體參數的穩定)或者在這兩個方面調節疾病、病症、綜合症或障礙。在又另一個實施方式中，「治療(treat、treating或treatment)」係指預防或延遲該疾病、病症、綜合症或障礙的發作或發展或進展。 As used herein, in one embodiment, the term "treat, treating or treatment" of any disease, disorder, syndrome or disorder refers to ameliorating the disease, disorder, syndrome or disorder (ie, slowing down or preventing Or reduce the development of the disease or at least one of its clinical symptoms). In another embodiment, "treat (treat, treating or treatment)" refers to alleviation or improvement of at least one physical parameter, including those that cannot be distinguished by the patient. In other embodiments, "treat (treat, treating or treatment)" refers to the physical aspects (such as the stability of discernible symptoms), the physiological aspects (such as the stability of physical parameters) or the regulation of the disease in both aspects , Illness, syndrome or disorder. In yet another embodiment, "treat (treat, treating or treatment)" refers to preventing or delaying the onset or development or progression of the disease, disorder, syndrome or disorder.

化合物A水合物的結晶形式I Crystalline Form I of Compound A Hydrate

1-(1-側氧基-1,2-二氫異喹啉-5-基)-5-(三氟甲基)-N-[2-(三氟甲基)吡啶-4-基]-1H-吡唑-4-甲醯胺具有以下結構並在本文中鑒定為「化合物A」。 1-(1-Pendant oxy-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl) -N -[2-(trifluoromethyl)pyridin-4-yl] -1 H -pyrazole-4-carboxamide has the following structure and is identified as "Compound A" herein.

Figure 109105620-A0202-12-0013-5
Figure 109105620-A0202-12-0013-5

化合物A可以例如藉由類似於WO 2018/119036(其藉由引用併入本文)的實例158中所述的程序來製備。實例158的程序已經被確定為提供化合物A水合物的結晶形式I。形式I表現出吸濕行為。 Compound A can be prepared, for example, by a procedure similar to that described in Example 158 of WO 2018/119036 (which is incorporated herein by reference). The procedure of Example 158 has been determined to provide crystalline Form I of Compound A hydrate. Form I exhibits hygroscopic behavior.

形式I可以藉由X射線粉末繞射圖來表徵。可以使用波長為1.5406的銅K-α X射線獲得該X射線粉末繞射圖。 Form I can be characterized by X-ray powder diffraction patterns. The X-ray powder diffraction pattern can be obtained using copper K-α X-rays with a wavelength of 1.5406.

該X射線粉末繞射圖包含在8.4、12.7、13.3和16.7°2θ±0.2°2θ處的峰。該X射線粉末繞射圖可進一步包含選自6.7、10.0、10.7、12.0、12.3、13.5、14.1、14.6、15.4、15.6、16.0、18.1、18.4、19.2、20.0、20.3、21.1、22.0和24.9°2θ±0.2°2θ的至少一個峰。 The X-ray powder diffraction pattern contains peaks at 8.4, 12.7, 13.3, and 16.7°2θ±0.2°2θ. The X-ray powder diffraction pattern may further comprise selected from 6.7, 10.0, 10.7, 12.0, 12.3, 13.5, 14.1, 14.6, 15.4, 15.6, 16.0, 18.1, 18.4, 19.2, 20.0, 20.3, 21.1, 22.0 and 24.9° At least one peak of 2θ±0.2°2θ.

形式I可進一步藉由X射線粉末繞射圖來表徵，該X射線粉末繞射圖具有選自表1中鑒定的那些峰的四個、五個、六個、七個、八個、九個或更多個峰。 Form I can be further characterized by an X-ray powder diffraction pattern having four, five, six, seven, eight, and nine peaks selected from those identified in Table 1. Or more peaks.

形式I可進一步藉由X射線粉末繞射圖來表徵，該X射線粉末繞射圖包含表1中鑒定的那些峰，其中該等峰的相對強度大於約2%，較佳的是大於約5%，更較佳的是大於約10%，更較佳的是大於約15%。 Form I can be further characterized by an X-ray powder diffraction pattern comprising those peaks identified in Table 1, wherein the relative intensity of these peaks is greater than about 2%, preferably greater than about 5 %, more preferably greater than about 10%, more preferably greater than about 15%.

形式I可進一步藉由基本上如圖7所示的X射線粉末繞射圖來表徵。 Form I can be further characterized by an X-ray powder diffraction pattern substantially as shown in FIG. 7.

形式I還可以藉由差示掃描量熱法熱譜圖(DSC)來表徵，該差示掃描量熱法熱譜圖包含起始溫度為66℃和峰值溫度為99℃的吸熱。該DSC可包含起始溫度為145℃和峰值溫度為157℃的第二吸熱。形式I可藉由基本上如圖8所示的DSC來表徵。 Form I can also be characterized by a differential scanning calorimetry thermogram (DSC), which contains an endotherm with an onset temperature of 66°C and a peak temperature of 99°C. The DSC may include a second endotherm with an onset temperature of 145°C and a peak temperature of 157°C. Form I can be characterized by a DSC substantially as shown in FIG. 8.

形式I可進一步藉由熱重量分析(TGA)來表徵。形式I可展現出基本上如圖9所示的TGA曲線。 Form I can be further characterized by thermogravimetric analysis (TGA). Form I can exhibit a TGA curve substantially as shown in FIG. 9.

形式I可進一步藉由動態蒸汽吸附(DVS)來表徵。形式I可展現出基本上如圖10所示的DVS等溫線圖。 Form I can be further characterized by dynamic vapor adsorption (DVS). Form I can exhibit a DVS isotherm diagram substantially as shown in FIG. 10.

化合物A一水合物的結晶形式III Crystal form III of compound A monohydrate

形式III表現出非吸濕行為(在80%的相對濕度下吸水率小於0.2%)。與水合物形式I不同，形式III避免了在低相對濕度(例如，相對濕度為20%或更低)下水的損失。該等係活性藥物成分(具體是旨在用於固體劑型的那些)中的期望特性。當避免含水量變化時，可以分配精確量的化合物A，並且稱重錯誤可被避免(例如，在製備配製物或劑型時)。 Form III exhibits non-hygroscopic behavior (water absorption is less than 0.2% at 80% relative humidity). Unlike hydrate form I, form III avoids water loss at low relative humidity (for example, relative humidity of 20% or lower). These are the desired properties in the active pharmaceutical ingredients, specifically those intended for solid dosage forms. When avoiding changes in water content, precise amounts of Compound A can be dispensed, and weighing errors can be avoided (for example, when preparing formulations or dosage forms).

形式III可以藉由X射線粉末繞射圖來表徵。可以使用波長為1.5406的銅K-α X射線獲得該X射線粉末繞射圖。 Form III can be characterized by X-ray powder diffraction patterns. The X-ray powder diffraction pattern can be obtained using copper K-α X-rays with a wavelength of 1.5406.

該X射線粉末繞射圖包含在16.4、23.7和25.7°2θ±0.2°2θ處的峰。該X射線粉末繞射圖可進一步包含在13.6、17.9、22.6、24.5、25.2和27.1°2θ±0.2°2θ處的峰。該X射線粉末繞射圖可進一步包含選自8.3、8.6、11.5、14.0、15.4、17.5、19.7、22.0、22.2、24.0和29.9°2θ±0.2°2θ的至少一個峰。 The X-ray powder diffraction pattern contains peaks at 16.4, 23.7, and 25.7°2θ±0.2°2θ. The X-ray powder diffraction pattern may further include peaks at 13.6, 17.9, 22.6, 24.5, 25.2, and 27.1°2θ±0.2°2θ. The X-ray powder diffraction pattern may further include at least one peak selected from 8.3, 8.6, 11.5, 14.0, 15.4, 17.5, 19.7, 22.0, 22.2, 24.0 and 29.9°2θ±0.2°2θ.

該X射線粉末繞射圖可包含在8.3、8.6、11.5、13.6、14.0、15.4、16.4、17.5、17.9、19.7、22.6、23.7、24.5、25.2、25.7和27.1°2θ±0.2°2θ處的峰。 The X-ray powder diffraction pattern can contain peaks at 8.3, 8.6, 11.5, 13.6, 14.0, 15.4, 16.4, 17.5, 17.9, 19.7, 22.6, 23.7, 24.5, 25.2, 25.7 and 27.1°2θ±0.2°2θ .

該X射線粉末繞射圖可包含在11.5、16.4、19.7、23.7和25.7°2θ±0.2°2θ處的峰。 The X-ray powder diffraction pattern may include peaks at 11.5, 16.4, 19.7, 23.7, and 25.7°2θ±0.2°2θ.

形式III可進一步藉由X射線粉末繞射圖來表徵，該X射線粉末繞射圖具有選自表2中鑒定的那些峰的四個、五個、六個、七個、八個、九個或更多個峰。化合物A一水合物形式III可進一步藉由X射線粉末繞射圖來表徵，該X射線粉末繞射圖包含表2中鑒定的那些峰，其中該等峰的相對強度大於約2%，較佳的是大於約5%，更較佳的是大於約10%，更較佳的是大於約15%。然而，技術人員將認識到，該等峰的相對強度在不同樣品之間以及同一樣品的不同測量值之間可能會有所不同。 Form III can be further characterized by an X-ray powder diffraction pattern having four, five, six, seven, eight, and nine peaks selected from those identified in Table 2. Or more peaks. Compound A monohydrate form III can be further characterized by an X-ray powder diffraction pattern, which includes those peaks identified in Table 2, wherein the relative intensity of these peaks is greater than about 2%, preferably It is greater than about 5%, more preferably greater than about 10%, more preferably greater than about 15%. However, the skilled person will recognize that the relative intensities of the peaks may vary between different samples and between different measurements of the same sample.

形式III可進一步藉由基本上如圖1所示的X射線粉末繞射圖來表徵。 Form III can be further characterized by an X-ray powder diffraction pattern substantially as shown in FIG. 1.

形式III還可以藉由差示掃描量熱法熱譜圖(DSC)來表徵，該差示掃描量熱法熱譜圖包含起始溫度為142℃和峰值溫度為158℃的吸熱。形式III可藉由基本上如圖2所示的差示掃描量熱法熱譜圖來表徵。 Form III can also be characterized by a differential scanning calorimetry thermogram (DSC), which contains an endotherm with an onset temperature of 142°C and a peak temperature of 158°C. Form III can be characterized by a differential scanning calorimetry thermogram substantially as shown in FIG. 2.

形式III可進一步藉由熱重量分析(TGA)來表徵。形式III可展現出基本上如圖3所示的TGA曲線。 Form III can be further characterized by thermogravimetric analysis (TGA). Form III can exhibit a TGA curve substantially as shown in FIG. 3.

形式III可進一步藉由DVS來表徵。形式III可展現出基本上如圖4所示的DVS等溫線圖。圖4的DVS等溫線圖顯示出形式III係非吸濕的。 Form III can be further characterized by DVS. Form III can exhibit a DVS isotherm diagram substantially as shown in FIG. 4. The DVS isotherm diagram of Figure 4 shows that Form III is non-hygroscopic.

形式III的製備 Preparation of Form III

化合物A一水合物的形式III可以藉由從合適選擇的溶劑混合物重結晶化合物A或其水合物或溶劑化物(例如，化合物A水合物結晶形式I)而製備。 Form III of Compound A monohydrate can be prepared by recrystallizing Compound A or a hydrate or solvate thereof from a suitably selected solvent mixture (e.g., Compound A hydrate crystalline form I).

化合物A一水合物的形式III可以藉由如下方法製備，該方法包括以下步驟：a)將化合物A或其水合物或溶劑化物添加至乙酸乙酯和乙醇的混合物中，並加熱至從約30℃至溶劑回流溫度範圍內的溫度；b)將水添加至該混合物中並過濾出任何沈澱物，維持所述溫度；c)將正庚烷添加至該混合物中，用結晶形式III進行晶種接種，並維持所述溫度；和d)冷卻至室溫，以產出該結晶形式的沈澱物；其中水的量相對於溶劑的總重量為從約0.1w/w%至約3w/w%；具體地，其中水的量相對於溶劑的總重量為從約1.0w/w%至約3w/w%。 Form III of compound A monohydrate can be prepared by the following method, which includes the following steps: a) adding compound A or its hydrate or solvate to a mixture of ethyl acetate and ethanol, and heating to about 30 Temperature in the range of ℃ to the reflux temperature of the solvent; b) Add water to the mixture and filter out any precipitate to maintain the temperature; c) Add n-heptane to the mixture and seed crystal form III Inoculate and maintain the temperature; and d) cool to room temperature to produce a precipitate in the crystalline form; wherein the amount of water relative to the total weight of the solvent is from about 0.1w/w% to about 3w/w% ; Specifically, wherein the amount of water relative to the total weight of the solvent is from about 1.0 w/w% to about 3 w/w%.

在一個實施方式中，水的量相對於溶劑的總重量為至少0.3w/w%，具體是0.4w/w%，更具體是至少0.8w/w%，甚至更具體是至少1.0w/w%。在一個實施方式中，水的量相對於該反應混合物的總質量為至少0.3w/w%，具體是0.4w/w%，具體是至少0.8w/w%，甚至更具體是至少1.0w/w%。在一個實施方式中，該反應混合物應含有超過化合物A量的0.038倍的水量。 In one embodiment, the amount of water relative to the total weight of the solvent is at least 0.3w/w%, specifically 0.4w/w%, more specifically at least 0.8w/w%, even more specifically at least 1.0w/w %. In one embodiment, the amount of water relative to the total mass of the reaction mixture is at least 0.3w/w%, specifically 0.4w/w%, specifically at least 0.8w/w%, even more specifically at least 1.0w/ w%. In one embodiment, the reaction mixture should contain an amount of water in excess of 0.038 times the amount of compound A.

在一個實施方式中，水的量相對於溶劑的總重量最大為3.0w/w%、2.5w/w%、2.0w/w%、1.5w/w%或1.0w/w%。 In one embodiment, the amount of water relative to the total weight of the solvent is at most 3.0w/w%, 2.5w/w%, 2.0w/w%, 1.5w/w% or 1.0w/w%.

在一個實施方式中，水的量相對於溶劑的總重量為1.0w/w%。在一個實施方式中，水的量相對於溶劑的總重量為從約0.3w/w%至約1.5w/w%。在一個實施方式中，水的量相對於溶劑的總重量為從0.3w/w%至1.5w/w%。 In one embodiment, the amount of water relative to the total weight of the solvent is 1.0 w/w%. In one embodiment, the amount of water is from about 0.3 w/w% to about 1.5 w/w% relative to the total weight of the solvent. In one embodiment, the amount of water is from 0.3 w/w% to 1.5 w/w% relative to the total weight of the solvent.

可替代地，化合物A一水合物的形式III可以藉由如下方法製備，該方法包括以下步驟：a)將化合物A或其水合物或溶劑化物添加至水和異丙醇的混合物中，並加熱至從約30℃至溶劑回流溫度範圍內的溫度；b)將正庚烷添加至該混合物中，用結晶形式III進行晶種接種，並維持所述溫度；和c)冷卻至室溫，以產出該結晶形式的沈澱物；其中水的量相對於溶劑的總重量為從約1.0w/w%至約6.0w/w%。 Alternatively, Form III of Compound A monohydrate can be prepared by the following method, which includes the following steps: a) Adding Compound A or its hydrate or solvate to a mixture of water and isopropanol and heating To a temperature ranging from about 30°C to the reflux temperature of the solvent; b) adding n-heptane to the mixture, seeding with crystalline form III, and maintaining the temperature; and c) cooling to room temperature to The precipitate in the crystalline form is produced; wherein the amount of water is from about 1.0 w/w% to about 6.0 w/w% relative to the total weight of the solvent.

在一個實施方式中，水的量相對於溶劑的總重量為至少2.0w/w%，具體是2.5w/w%，更具體是至少2.8w/w%，甚至更具體是至少3.0w/w%。在一個實施方式中，水的量相對於該反應混合物的總質量為至少2.0w/w%，具體是2.5w/w%，更具體是至少2.8w/w%，甚至更具體是至少3.0w/w%。 In one embodiment, the amount of water relative to the total weight of the solvent is at least 2.0w/w%, specifically 2.5w/w%, more specifically at least 2.8w/w%, even more specifically at least 3.0w/w %. In one embodiment, the amount of water relative to the total mass of the reaction mixture is at least 2.0w/w%, specifically 2.5w/w%, more specifically at least 2.8w/w%, even more specifically at least 3.0w /w%.

在一個實施方式中，水的量相對於溶劑的總重量最大為5.5w/w%、5.0w/w%、4.5w/w%、4.0w/w%或3.5w/w%。 In one embodiment, the amount of water relative to the total weight of the solvent is at most 5.5w/w%, 5.0w/w%, 4.5w/w%, 4.0w/w%, or 3.5w/w%.

在一個實施方式中，水的量相對於溶劑的總重量為3.5w/w%。在一個實施方式中，水的量相對於溶劑的總重量為從約2.0w/w%至約5.0w/w%。在一個實施方式中，水的量相對於溶劑的總重量為從2.0w/w%至5.0w/w%。 In one embodiment, the amount of water relative to the total weight of the solvent is 3.5 w/w%. In one embodiment, the amount of water is from about 2.0 w/w% to about 5.0 w/w% relative to the total weight of the solvent. In one embodiment, the amount of water is from 2.0 w/w% to 5.0 w/w% relative to the total weight of the solvent.

技術人員將認識到反應混合物中必須存在足夠的水，並且具體的最小水量取決於化合物A的量。如果含水量太高，化合物A的形式I可以代替化合物A的形式III，在這種情況下，必須降低含水量。 The skilled person will recognize that sufficient water must be present in the reaction mixture, and the specific minimum amount of water depends on the amount of compound A. If the water content is too high, Form I of Compound A can replace Form III of Compound A, in which case the water content must be reduced.

上文說明書中提及的溶劑的總重量係指其中化合物A或其水合物(例如，一水合物)或溶劑的形式III係可溶的溶劑的總重量，不包括反溶劑(水和正庚烷)。 The total weight of the solvent mentioned in the above specification refers to the total weight of the solvent in which compound A or its hydrate (e.g., monohydrate) or the form III of the solvent is soluble, excluding the antisolvent (water and n-heptane) ).

技術人員還將理解，如果在形式III的製備中用作起始材料的化合物A係水合物，則在來自起始材料的系統中已經有一定量的水可用。相反，如果使用化合物A的非水合物溶劑化物作為起始材料，則技術人員將清楚，必須將更多的水添加到該混合物中，以獲得所需的w/w%。 The skilled person will also understand that if the compound A-based hydrate is used as the starting material in the preparation of Form III, a certain amount of water is already available in the system from the starting material. In contrast, if a non-hydrate solvate of compound A is used as the starting material, the skilled person will know that more water must be added to the mixture to obtain the desired w/w%.

化合物A或其水合物或溶劑化物可包含水合物結晶形式I。在本文所述的方法中將該混合物加熱至的溫度可以為從約40℃至約55℃。在步驟a)中，可以將該混合物加熱至少30分鐘或至少1小時。在其中添加正庚烷的步驟中，可以在添加正庚烷之後將結晶形式III晶種材料添加至該混合物中，並且可以將溫度維持至少4小時。可以經至少5小時，具體經至少8小時，更具體經至少10小時緩慢添加另外部分的正庚烷。在其中將該混合物冷卻至室溫的步驟中，可以將該混合物在室溫下攪拌至少12小時。 Compound A or a hydrate or solvate thereof may comprise hydrate crystalline form I. The temperature to which the mixture is heated in the methods described herein can be from about 40°C to about 55°C. In step a), the mixture can be heated for at least 30 minutes or at least 1 hour. In the step where n-heptane is added, the crystalline form III seed material may be added to the mixture after the addition of n-heptane, and the temperature may be maintained for at least 4 hours. The additional portion of n-heptane may be slowly added over at least 5 hours, specifically at least 8 hours, more specifically at least 10 hours. In the step in which the mixture is cooled to room temperature, the mixture may be stirred at room temperature for at least 12 hours.

本文所述的方法可進一步包括過濾出沈澱物並用正庚烷洗滌所述沈澱物的步驟。該方法可進一步包括在真空下，視需要在從約45℃至約55℃的溫度下乾燥該沈澱物的步驟。 The method described herein may further include the step of filtering out the precipitate and washing the precipitate with n-heptane. The method may further include the step of drying the precipitate at a temperature of from about 45°C to about 55°C under vacuum, if necessary.

化合物A一水合物的形式III可以藉由如下方法製備，該方法包括以下步驟：a)將化合物A或其水合物或溶劑化物添加至乙酸乙酯或乙酸異丙酯中；和b)在從約30℃至溶劑回流溫度範圍內的溫度下攪拌所得懸浮液，以產出化合物A形式III的結晶一水合物的沈澱物。化合物A或其水合物或溶劑化物可包含水合物結晶形式I。 Form III of compound A monohydrate can be prepared by a method comprising the following steps: a) adding compound A or its hydrate or solvate to ethyl acetate or isopropyl acetate; and b) from The resulting suspension is stirred at a temperature in the range of about 30°C to the reflux temperature of the solvent to produce a precipitate of the crystalline monohydrate of Compound A Form III. Compound A or a hydrate or solvate thereof may comprise hydrate crystalline form I.

將該混合物加熱至的溫度可以為從約40℃至約溶劑回流溫度或從約50℃至約溶劑回流溫度。將該混合物加熱至的溫度可以為約60℃。可以將懸浮液攪拌至少1天、至少2天、至少3天、至少4天或至少5天。 The temperature to which the mixture is heated can be from about 40°C to about the solvent reflux temperature or from about 50°C to about the solvent reflux temperature. The temperature to which the mixture is heated may be about 60°C. The suspension can be stirred for at least 1 day, at least 2 days, at least 3 days, at least 4 days, or at least 5 days.

該方法可進一步包括過濾出該沈澱物的步驟c)。該方法可進一步包括在真空下，視需要在從約45℃至約55℃的溫度下乾燥該沈澱物的步驟d)。 The method may further include the step c) of filtering out the precipitate. The method may further include a step d) of drying the precipitate at a temperature of from about 45°C to about 55°C under vacuum, if necessary.

可替代地，化合物A一水合物的形式III可以藉由如下方法製備，該方法包括以下步驟：a)將化合物A或其水合物或溶劑化物添加至水和異丙醇的混合物中；和b)在從約30℃至溶劑回流溫度範圍內的溫度下攪拌所得懸浮液，以產出化合物A形式III的結晶一水合物的沈澱物。化合物A或其水合物或溶劑化物可包含水合物結晶形式I。 Alternatively, the form III of compound A monohydrate can be prepared by a method comprising the following steps: a) adding compound A or its hydrate or solvate to a mixture of water and isopropanol; and b ) Stir the resulting suspension at a temperature ranging from about 30°C to the reflux temperature of the solvent to produce a precipitate of the crystalline monohydrate of Compound A Form III. Compound A or a hydrate or solvate thereof may comprise hydrate crystalline form I.

將該混合物加熱至的溫度可以為從約40℃至約溶劑回流溫度或從約50℃至約溶劑回流溫度。將該混合物加熱至的溫度可以為約60℃。可以將懸浮液攪拌至少1天、至少2天、至少3天、至少4天或至少5天。 The temperature to which the mixture is heated can be from about 40°C to about the solvent reflux temperature or from about 50°C to about the solvent reflux temperature. The temperature to which the mixture is heated may be about 60°C. The suspension can be stirred for at least 1 day, at least 2 days, at least 3 days, at least 4 days, or at least 5 days.

該方法可進一步包括過濾出該沈澱物的步驟c)。該方法可進一步包括在真空下，視需要在從約45℃至約55℃的溫度下乾燥該沈澱物的步驟d)。 The method may further include the step c) of filtering out the precipitate. The method may further include a step d) of drying the precipitate at a temperature of from about 45°C to about 55°C under vacuum, if necessary.

組成物 Composition

即使本發明的實施方式的化合物可以單獨投與，但就預期的投與途徑和標準藥物或獸醫實踐而言，它們通常與所選擇的藥學上可接受的載體、藥學上可接受的賦形劑、和/或藥學上可接受的稀釋劑混合投與。因此，本發明的具體實施方式關於藥物組成物和獸醫組成物，該等藥物組成物和獸醫組成物包含化合物A一水合物的結晶形式III以及至少一種藥學上可接受的載體、藥學上可接受的賦形劑、和/或藥學上可接受的稀釋劑。 Even though the compounds of the embodiments of the present invention can be administered alone, they are usually combined with selected pharmaceutically acceptable carriers and pharmaceutically acceptable excipients in terms of the expected route of administration and standard drugs or veterinary practice. , And/or a pharmaceutically acceptable diluent for mixed administration. Therefore, the specific embodiments of the present invention relate to pharmaceutical compositions and veterinary compositions, which comprise the crystalline form III of Compound A monohydrate and at least one pharmaceutically acceptable carrier, pharmaceutically acceptable Excipients, and/or pharmaceutically acceptable diluents.

作為實例，在本發明的實施方式的藥物組成物中，化合物A一水合物的結晶形式III可以與任何合適的一種或多種黏合劑、一種或多種潤滑劑、一種或多種懸浮劑、一種或多種包衣劑、一種或多種增溶劑、及其組合混合。 As an example, in the pharmaceutical composition of the embodiment of the present invention, the crystalline form III of Compound A monohydrate can be combined with any suitable one or more binders, one or more lubricants, one or more suspending agents, one or more Coating agents, one or more solubilizers, and combinations thereof are mixed.

適當時，含有本發明的結晶形式的固體口服劑型(例如片劑或膠囊劑)可以一次以至少一種劑型投與。還有可能以緩釋配製物的形式投與該結晶形式。 Where appropriate, solid oral dosage forms (for example, tablets or capsules) containing the crystalline form of the present invention may be administered in at least one dosage form at a time. It is also possible to administer the crystalline form in the form of a sustained release formulation.

可以投與該結晶形式的另外的口服形式包括酏劑、溶液、糖漿劑、和懸浮液；每種形式都視需要含有調味劑和著色劑。 Additional oral forms in which the crystalline form can be administered include elixirs, solutions, syrups, and suspensions; each form contains flavoring and coloring agents as needed.

可替代地，該結晶形式可以藉由(氣管內或鼻內)吸入投與或者以栓劑或***栓的形式投與，或者可以以洗劑、溶液、霜劑、軟膏或撲粉的形式局部應用。例如，可以將其摻入霜劑中，該霜劑包含聚乙二醇或液體石蠟的水乳液，由其組成和/或基本上由其組成。也可以將其以霜劑重量的約1%至約10%之間的濃度摻入軟膏中，該軟膏包含蠟或軟石蠟基質以及可能需要的任何穩定劑和防腐劑，由其組成和/或基本上由其組成。替代的投與方式包括藉由使用皮膚或透皮貼劑的透皮投與。 Alternatively, the crystalline form can be administered by inhalation (intratracheal or intranasal) or in the form of suppositories or vaginal suppositories, or can be applied topically in the form of lotions, solutions, creams, ointments or dusting powder. For example, it can be incorporated into a cream comprising, consisting of and/or consisting essentially of an aqueous emulsion of polyethylene glycol or liquid paraffin. It can also be incorporated into an ointment at a concentration between about 1% and about 10% by weight of the cream, the ointment comprising a wax or soft paraffin base and any stabilizers and preservatives that may be required, consisting of and/or Basically consists of it. Alternative administration methods include transdermal administration by using skin or transdermal patches.

本發明的藥物組成物(以及單獨的一水合物結晶形式III)也可以腸胃外注射，例如，海綿竇內、靜脈內、肌肉內、皮下、皮內或鞘內注射。在這種情況下，該等組成物還將包括合適的載體、合適的賦形劑、和合適的稀釋劑中的至少一種。 The pharmaceutical composition of the present invention (and the monohydrate crystalline form III alone) can also be injected parenterally, for example, intracavernous sinus, intravenous, intramuscular, subcutaneous, intradermal or intrathecal injection. In this case, the compositions will also include at least one of a suitable carrier, a suitable excipient, and a suitable diluent.

對於腸胃外投與，本發明的藥物組成物最好以無菌水溶液的形式使用，該無菌水溶液可含有其他物質，例如足夠的鹽和單糖，從而使該溶液與血液等滲。 For parenteral administration, the pharmaceutical composition of the present invention is preferably used in the form of a sterile aqueous solution, which may contain other substances, such as sufficient salts and monosaccharides, to make the solution isotonic with blood.

對於經頰或舌下投與，本發明的藥物組成物可以按以下形式投與：能夠按照常規方式進行配製的片劑或錠劑的形式。 For buccal or sublingual administration, the pharmaceutical composition of the present invention can be administered in the form of tablets or lozenges that can be formulated in a conventional manner.

作為另外的實例，根據常規藥用化合技術，含有該結晶形式作為活性藥物成分的藥物組成物可以藉由將該結晶形式與藥學上可接受的載體、藥學上可接受的稀釋劑、和/或藥學上可接受的賦形劑混合來製備。載體、賦形劑和稀釋劑可以採用多種形式，這取決於期望的投與途徑(例如，口服、腸胃外等)。因此，對於液體口服製劑(例如懸浮液、糖漿劑、酏劑和溶液)，合適的載體、賦形劑和稀釋劑包括水、甘油、油類、醇類、調味劑、防腐劑、穩定劑、著色劑等等；對於固體口服製劑(例如散劑、膠囊劑和片劑)，合適的載體、賦形劑和稀釋劑包括澱粉、糖、稀釋劑、粒化劑、潤滑劑、黏合劑、崩解劑等等。固體口服製劑還可以視需要用例如糖的物質包衣，或腸溶包衣以調節 吸收和崩解的主要部位。對於腸胃外投與，載體、賦形劑和稀釋劑通常將包括無菌水，並且可以添加其他成分以增加該組成物的溶解性和保存。也可以利用水載體以及適當的添加劑(例如增溶劑和防腐劑)來製備可注射的懸浮液或溶液。 As another example, according to conventional pharmaceutical compounding techniques, a pharmaceutical composition containing the crystalline form as an active pharmaceutical ingredient can be prepared by combining the crystalline form with a pharmaceutically acceptable carrier, a pharmaceutically acceptable diluent, and/or Pharmaceutically acceptable excipients are mixed to prepare. Carriers, excipients, and diluents can take a variety of forms, depending on the desired route of administration (for example, oral, parenteral, etc.). Therefore, for liquid oral preparations (such as suspensions, syrups, elixirs, and solutions), suitable carriers, excipients, and diluents include water, glycerin, oils, alcohols, flavoring agents, preservatives, stabilizers, Coloring agents, etc.; for solid oral preparations (such as powders, capsules, and tablets), suitable carriers, excipients and diluents include starch, sugar, diluents, granulating agents, lubricants, binders, and disintegrants Agent and so on. The solid oral preparation can also be coated with substances such as sugar or enteric coating as needed to adjust The main part of absorption and disintegration. For parenteral administration, carriers, excipients, and diluents will generally include sterile water, and other ingredients may be added to increase the solubility and storage of the composition. It is also possible to prepare injectable suspensions or solutions using water carriers and appropriate additives (such as solubilizers and preservatives).

對於平均(70kg)的人類，在每天約1至約(4x)的方案中，治療有效量的化合物A一水合物的結晶形式III或其藥物組成物包括如下劑量範圍的活性藥物成分：從約0.1mg至約3000mg或其中的任何具體量或範圍，特別是從約1mg至約1000mg或其中的任何具體量或範圍，或者更特別是從約10mg至約500mg或其中的任何具體量或範圍；然而，熟悉該項技術者很清楚，所述結晶形式的治療有效量將隨著所治療的疾病、綜合症、病症和障礙而變化。 For an average (70kg) human, in a regimen of about 1 to about (4x) per day, a therapeutically effective amount of Compound A monohydrate crystalline form III or its pharmaceutical composition includes the active pharmaceutical ingredient in the following dosage range: from about 0.1 mg to about 3000 mg or any specific amount or range therein, particularly from about 1 mg to about 1000 mg or any specific amount or range therein, or more particularly from about 10 mg to about 500 mg or any specific amount or range therein; However, it is clear to those skilled in the art that the therapeutically effective amount of the crystalline form will vary with the disease, syndrome, disorder, and disorder being treated.

對於口服投與，具體是以含有約1.0、約10、約50、約100、約150、約200、約250、和約500毫克的化合物A一水合物的結晶形式III的片劑形式提供藥物組成物。 For oral administration, the drug is specifically provided in the form of a tablet containing about 1.0, about 10, about 50, about 100, about 150, about 200, about 250, and about 500 mg of Compound A monohydrate crystal form III Composition.

對於口服投與，具體是以含有約1.0、約10、約50、約100、約150、約200、約250、和約500毫克的化合物A一水合物的結晶形式III的膠囊劑形式提供藥物組成物。 For oral administration, the drug is specifically provided in the form of a capsule containing about 1.0, about 10, about 50, about 100, about 150, about 200, about 250, and about 500 mg of Compound A monohydrate crystal form III Composition.

本發明的一個實施方式關於用於口服投與的藥物組成物，該藥物組成物包含從約25mg至約500mg的量的化合物A一水合物的結晶形式III。 One embodiment of the present invention relates to a pharmaceutical composition for oral administration, the pharmaceutical composition comprising the crystalline form III of Compound A monohydrate in an amount of from about 25 mg to about 500 mg.

有利的是，化合物A一水合物的結晶形式III可以以單日劑量投與，或者總日劑量可以以每日兩次、三次和4x的分開劑量投與。 Advantageously, the crystalline form III of Compound A monohydrate can be administered in a single daily dose, or the total daily dose can be administered in divided doses of two, three, and 4x daily.

有待投與的結晶形式的最佳劑量可以容易地確定，並且將隨所使用的具體化合物，投與方式，製劑的強度，以及疾病、綜合症、病症或障礙的進展而變化。此外，與所治療的具體受試者相關的因素，包括受試者性別、年齡、體重、飲食以及投與時間，將導致需要調節劑量以達到適當的治療水平和 期望的治療效果。因此，上述劑量係平均情況的示例。當然，可存在其中應當使用更高或更低的劑量範圍的個別情況，並且該等在本發明的範圍內。 The optimal dosage of the crystalline form to be administered can be easily determined, and will vary with the specific compound used, the mode of administration, the strength of the formulation, and the progression of the disease, syndrome, disorder, or disorder. In addition, factors related to the specific subject being treated, including the subject’s gender, age, weight, diet, and time of administration, will result in the need to adjust the dosage to achieve an appropriate level of treatment and The desired therapeutic effect. Therefore, the above dose is an example of an average situation. Of course, there may be individual cases where higher or lower dosage ranges should be used, and such are within the scope of the present invention.

治療方法 treatment method

每當有需要的受試者需要使用結晶形式時，化合物A一水合物的結晶形式III可以以前述組成物和劑量方案中的任一種或者藉由本領域建立的那些組成物和劑量方案來投與。 Whenever a subject in need needs to use the crystalline form, the crystalline form III of Compound A monohydrate can be administered in any of the aforementioned compositions and dosage regimens or by those compositions and dosage regimens established in the art .

結晶形式III可用於治療、改善和/或預防受MALT1的抑制的影響的疾病、綜合症、病症或障礙的方法中。這類方法包括向對此類治療、改善和/或預防有需要的受試者(包括動物、哺乳動物和人類)投與治療有效量的化合物A一水合物的結晶形式III，由其組成和/或基本上由其組成。 The crystalline form III can be used in a method of treating, ameliorating and/or preventing diseases, syndromes, disorders or disorders affected by the inhibition of MALT1. Such methods include administering a therapeutically effective amount of compound A monohydrate crystalline form III to subjects (including animals, mammals, and humans) in need of such treatment, improvement, and/or prevention, consisting of and / Or basically consist of it.

本發明的一個實施方式關於在有需要的受試者(包括對此類治療有需要的動物、哺乳動物和人類)中治療MALT1依賴性或MALT1介導的疾病或病症的方法，該方法包括向該受試者投與治療有效量的化合物A一水合物的結晶形式III。 One embodiment of the present invention relates to a method of treating MALT1-dependent or MALT1-mediated diseases or disorders in subjects in need (including animals, mammals and humans in need of such treatment), the method comprising: The subject is administered a therapeutically effective amount of the crystalline form III of Compound A monohydrate.

在另一個實施方式中，該MALT1依賴性或MALT1介導的疾病或病症選自造血起源的癌症或實體瘤，例如慢性髓細胞性白血病、髓樣白血病、非何杰金氏淋巴瘤、以及其他B細胞淋巴瘤。 In another embodiment, the MALT1-dependent or MALT1-mediated disease or disorder is selected from cancers or solid tumors of hematopoietic origin, such as chronic myeloid leukemia, myeloid leukemia, non-Hodgkin’s lymphoma, and others B cell lymphoma.

具體地，化合物A一水合物的結晶形式III可用於治療或改善疾病、綜合症、病症或障礙，例如彌漫性大B細胞淋巴瘤(DLBCL)、外膜細胞淋巴瘤(MCL)、濾泡性淋巴瘤(FL)、以及黏膜相關淋巴組織(MALT)淋巴瘤。 Specifically, the crystalline form III of compound A monohydrate can be used to treat or ameliorate diseases, syndromes, disorders or disorders, such as diffuse large B-cell lymphoma (DLBCL), adventitia cell lymphoma (MCL), follicular Lymphoma (FL), and Mucosa Associated Lymphoid Tissue (MALT) lymphoma.

更特別地，化合物A一水合物的結晶形式III可用於治療或改善彌漫性大B細胞淋巴瘤(DLBCL)、外膜細胞淋巴瘤(MCL)、濾泡性淋巴瘤(FL)、以及黏膜相關淋巴組織(MALT)淋巴瘤，這種治療或改善包括向有需要的受試者投與治療有效量的所述結晶形式。 More specifically, the crystalline form III of Compound A monohydrate can be used to treat or ameliorate diffuse large B-cell lymphoma (DLBCL), adventitia cell lymphoma (MCL), follicular lymphoma (FL), and mucosal-related Lymphoid tissue (MALT) lymphoma, such treatment or improvement includes administering a therapeutically effective amount of the crystalline form to a subject in need.

另外，化合物A一水合物的結晶形式III可用於治療或改善免疫性疾病、綜合症、障礙或病症，該免疫性疾病、綜合症、障礙或病症選自由以下項組成之群組：類風濕性關節炎(RA)、牛皮癬性關節炎(PsA)、牛皮癬(Pso)、潰瘍性結腸炎(UC)、克羅恩氏病、全身性紅斑狼瘡(SLE)、氣喘、以及慢性阻塞性肺病(COPD)。 In addition, the crystalline form III of compound A monohydrate can be used to treat or ameliorate immune diseases, syndromes, disorders or conditions, which are selected from the group consisting of: rheumatoid Arthritis (RA), psoriatic arthritis (PsA), psoriasis (Pso), ulcerative colitis (UC), Crohn's disease, systemic lupus erythematosus (SLE), asthma, and chronic obstructive pulmonary disease (COPD) ).

在一個實施方式中，可受益於用化合物A一水合物(MALT1抑制劑)的結晶形式III治療的癌症包括但不限於淋巴瘤，白血病，癌和肉瘤，例如非何杰金氏淋巴瘤(NHL)、B細胞NHL、彌漫性大B細胞淋巴瘤(DLBCL)、外膜細胞淋巴瘤(MCL)、濾泡性淋巴瘤(FL)、黏膜相關淋巴組織(MALT)淋巴瘤、邊緣區淋巴瘤、T細胞淋巴瘤、何杰金氏淋巴瘤、柏基特氏淋巴瘤、多發性骨髓瘤、慢性淋巴細胞性白血病(CLL)、小淋巴細胞淋巴瘤(SLL)、瓦爾登斯特倫巨球蛋白血症、淋巴母細胞T細胞白血病、慢性髓細胞性白血病(CML)、毛細胞白血病、急性淋巴母細胞T細胞白血病、漿細胞瘤、免疫母細胞性大細胞白血病、巨核母細胞性白血病、急性巨核細胞白血病、前髓細胞白血病、紅白血病、腦癌(神經膠質瘤)、惡性膠質瘤、乳腺癌、結腸直腸癌/結腸癌、***癌、肺癌(包括非小細胞肺癌)、胃癌、子宮內膜癌、黑素瘤、胰臟癌、肝癌、腎癌(kidney cancer)、鱗狀細胞癌、卵巢癌、肉瘤、骨肉瘤、甲狀腺癌、膀胱癌、頭頸癌、睾丸癌、尤因氏肉瘤、橫紋肌肉瘤、成神經管細胞瘤、神經母細胞瘤、子宮頸癌、腎癌(renal cancer)、尿路上皮癌、外陰癌、食管癌、唾液腺癌、鼻咽癌、頰癌、口腔癌、以及GIST(胃腸道間質瘤)。 In one embodiment, cancers that can benefit from treatment with compound A monohydrate (MALT1 inhibitor) crystalline form III include, but are not limited to, lymphoma, leukemia, carcinoma, and sarcoma, such as non-Hodgkin’s lymphoma (NHL ), B-cell NHL, diffuse large B-cell lymphoma (DLBCL), adventitia cell lymphoma (MCL), follicular lymphoma (FL), mucosa-associated lymphoid tissue (MALT) lymphoma, marginal zone lymphoma, T cell lymphoma, Hodgkin's lymphoma, Burkitt's lymphoma, multiple myeloma, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), Waldenstrom macroglobulin Acute lymphoblastic T-cell leukemia, lymphoblastic T-cell leukemia, chronic myelogenous leukemia (CML), hairy cell leukemia, acute lymphoblastic T-cell leukemia, plasmacytoma, immunoblastic large cell leukemia, megakaryoblastic leukemia, acute Megakaryocyte leukemia, promyelocytic leukemia, erythroleukemia, brain cancer (glioma), malignant glioma, breast cancer, colorectal cancer/colon cancer, prostate cancer, lung cancer (including non-small cell lung cancer), stomach cancer, intrauterine Membrane cancer, melanoma, pancreatic cancer, liver cancer, kidney cancer (kidney cancer), squamous cell cancer, ovarian cancer, sarcoma, osteosarcoma, thyroid cancer, bladder cancer, head and neck cancer, testicular cancer, Ewing's sarcoma, Rhabdomyosarcoma, medulloblastoma, neuroblastoma, cervical cancer, renal cancer, urothelial cancer, vulvar cancer, esophageal cancer, salivary gland cancer, nasopharyngeal cancer, buccal cancer, oral cancer, and GIST (Gastrointestinal Stromal Tumor).

在另一個實施方式中，化合物A一水合物的結晶形式III可用於治療免疫性疾病，包括但不限於自體免疫障礙和炎性障礙，例如關節炎、炎症性腸病、胃炎、強直性脊柱炎、潰瘍性結腸炎、胰腺炎、克羅恩氏病、乳糜瀉、多發性硬化症、全身性紅斑狼瘡、狼瘡性腎炎、風濕熱、痛風、器官或移植排斥、慢性同種異體移植排斥、急性或慢性移植物抗宿主病、皮炎(包括特應性 皮炎、皮肌炎、牛皮癬)、貝赫切特氏病、眼色素層炎、重症肌無力、格雷夫斯病、橋本甲狀腺炎、乾燥綜合症、起泡障礙、抗體介導的血管炎綜合症、免疫複合物血管炎、過敏障礙、氣喘、支氣管炎、慢性阻塞性肺病(COPD)、囊性纖維化、肺炎、肺部疾病(包括水腫、栓塞)、纖維化、類肉瘤病、高血壓和肺氣腫、矽肺、呼吸衰竭、急性呼吸窘迫症候群、BENTA疾病、鈹中毒、以及多肌炎。 In another embodiment, the crystalline form III of Compound A monohydrate can be used to treat immune diseases, including but not limited to autoimmune disorders and inflammatory disorders, such as arthritis, inflammatory bowel disease, gastritis, ankylosing spine Inflammation, ulcerative colitis, pancreatitis, Crohn's disease, celiac disease, multiple sclerosis, systemic lupus erythematosus, lupus nephritis, rheumatic fever, gout, organ or transplant rejection, chronic allograft rejection, acute Or chronic graft versus host disease, dermatitis (including atopic Dermatitis, dermatomyositis, psoriasis), Behçet’s disease, uveitis, myasthenia gravis, Graves’ disease, Hashimoto’s thyroiditis, Sjogren’s syndrome, blistering disorder, antibody-mediated vasculitis syndrome , Immune complex vasculitis, allergic disorders, asthma, bronchitis, chronic obstructive pulmonary disease (COPD), cystic fibrosis, pneumonia, lung diseases (including edema, embolism), fibrosis, sarcoidosis, hypertension and Emphysema, silicosis, respiratory failure, acute respiratory distress syndrome, BENTA disease, beryllium poisoning, and polymyositis.

本發明的一個實施方式關於治療疾病、綜合症、病症或障礙之方法，其中所述疾病、綜合症、病症或障礙受MALT1的抑制的影響，該方法包括向有需要的受試者投與治療有效量的化合物A一水合物的結晶形式III。 One embodiment of the present invention relates to a method for treating a disease, syndrome, disorder, or disorder, wherein the disease, syndrome, disorder, or disorder is affected by the inhibition of MALT1, and the method comprises administering treatment to a subject in need An effective amount of the crystalline form III of Compound A monohydrate.

在另外的實施方式中，該疾病、綜合症、病症或障礙選自由以下項組成之群組：彌漫性大B細胞淋巴瘤(DLBCL)、外膜細胞淋巴瘤(MCL)、濾泡性淋巴瘤(FL)、和黏膜相關淋巴組織(MALT)淋巴瘤、類風濕性關節炎(RA)、牛皮癬性關節炎(PsA)、牛皮癬(Pso)、潰瘍性結腸炎(UC)、克羅恩氏病、全身性紅斑狼瘡(SLE)、氣喘、以及慢性阻塞性肺病(COPD)。 In other embodiments, the disease, syndrome, disorder or disorder is selected from the group consisting of: diffuse large B-cell lymphoma (DLBCL), adventitia cell lymphoma (MCL), follicular lymphoma (FL), and mucosa associated lymphoid tissue (MALT) lymphoma, rheumatoid arthritis (RA), psoriatic arthritis (PsA), psoriasis (Pso), ulcerative colitis (UC), Crohn's disease , Systemic lupus erythematosus (SLE), asthma, and chronic obstructive pulmonary disease (COPD).

在另外的實施方式中，該疾病、綜合症、病症或障礙選自由以下項組成之群組：彌漫性大B細胞淋巴瘤(DLBCL)、外膜細胞淋巴瘤(MCL)、濾泡性淋巴瘤(FL)、黏膜相關淋巴組織(MALT)淋巴瘤、邊緣區淋巴瘤、慢性淋巴細胞性白血病(CLL)、小淋巴細胞淋巴瘤(SLL)、以及瓦爾登斯特倫巨球蛋白血症。 In other embodiments, the disease, syndrome, disorder or disorder is selected from the group consisting of: diffuse large B-cell lymphoma (DLBCL), adventitia cell lymphoma (MCL), follicular lymphoma (FL), Mucosa Associated Lymphoid Tissue (MALT) Lymphoma, Marginal Zone Lymphoma, Chronic Lymphocytic Leukemia (CLL), Small Lymphocytic Lymphoma (SLL), and Waldenstrom's Macroglobulinemia.

在一個實施方式中，本發明關於治療疾病、綜合症、病症或障礙的方法，該疾病、綜合症、病症或障礙選自由以下項組成之群組：彌漫性大B細胞淋巴瘤(DLBCL)、外膜細胞淋巴瘤(MCL)、濾泡性淋巴瘤(FL)、和黏膜相關淋巴組織(MALT)淋巴瘤、類風濕性關節炎(RA)、牛皮癬性關節炎(PsA)、牛皮癬(Pso)、潰瘍性結腸炎(UC)、克羅恩氏病、全身性紅斑狼 瘡(SLE)、氣喘、以及慢性阻塞性肺病(COPD)，該方法包括向有需要的受試者投與治療有效量的化合物A一水合物的結晶形式III。 In one embodiment, the present invention relates to a method of treating a disease, syndrome, disorder or disorder, the disease, syndrome, disorder or disorder selected from the group consisting of: diffuse large B-cell lymphoma (DLBCL), Adventitia cell lymphoma (MCL), follicular lymphoma (FL), and mucosal associated lymphoid tissue (MALT) lymphoma, rheumatoid arthritis (RA), psoriatic arthritis (PsA), psoriasis (Pso) , Ulcerative Colitis (UC), Crohn's Disease, Systemic Lupus For sores (SLE), asthma, and chronic obstructive pulmonary disease (COPD), the method comprises administering to a subject in need thereof a therapeutically effective amount of crystalline form III of Compound A monohydrate.

在另一個實施方式中，本發明關於治療疾病、綜合症、病症或障礙的方法，該疾病、綜合症、病症或障礙選自由以下項組成之群組：彌漫性大B細胞淋巴瘤(DLBCL)、外膜細胞淋巴瘤(MCL)、濾泡性淋巴瘤(FL)、黏膜相關淋巴組織(MALT)淋巴瘤、邊緣區淋巴瘤、慢性淋巴細胞性白血病(CLL)、小淋巴細胞淋巴瘤(SLL)、以及瓦爾登斯特倫巨球蛋白血症，該方法包括向有需要的受試者投與治療有效量的化合物A一水合物的結晶形式III。在另外的實施方式中，該疾病、綜合症、病症或障礙係非何杰金氏淋巴瘤(NHL)。在另外的實施方式中，該非何杰金氏淋巴瘤(NHL)係B細胞NHL。 In another embodiment, the present invention relates to a method of treating a disease, syndrome, disorder, or disorder, the disease, syndrome, disorder, or disorder selected from the group consisting of: Diffuse Large B-Cell Lymphoma (DLBCL) , Adventitia cell lymphoma (MCL), follicular lymphoma (FL), mucosa associated lymphoid tissue (MALT) lymphoma, marginal zone lymphoma, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL) ), and Waldenstrom's macroglobulinemia, the method comprising administering to a subject in need thereof a therapeutically effective amount of compound A monohydrate crystal form III. In another embodiment, the disease, syndrome, condition or disorder is non-Hodgkin's lymphoma (NHL). In another embodiment, the non-Hodgkin's lymphoma (NHL) is a B cell NHL.

在另一個實施方式中，本發明關於化合物A一水合物的結晶形式III用於製備在有需要的受試者中治療疾病、綜合症、障礙或病症的藥物，該疾病、綜合症、障礙或病症選自由以下項組成之群組：彌漫性大B細胞淋巴瘤(DLBCL)、外膜細胞淋巴瘤(MCL)、濾泡性淋巴瘤(FL)、和黏膜相關淋巴組織(MALT)淋巴瘤、類風濕性關節炎(RA)、牛皮癬性關節炎(PsA)、牛皮癬(Pso)、潰瘍性結腸炎(UC)、克羅恩氏病、全身性紅斑狼瘡(SLE)、氣喘、以及慢性阻塞性肺病(COPD)。 In another embodiment, the crystalline form III of the compound A monohydrate of the present invention is used to prepare a medicament for the treatment of a disease, syndrome, disorder or condition in a subject in need thereof, the disease, syndrome, disorder or The condition is selected from the group consisting of: diffuse large B-cell lymphoma (DLBCL), adventitia cell lymphoma (MCL), follicular lymphoma (FL), and mucosal associated lymphoid tissue (MALT) lymphoma, Rheumatoid arthritis (RA), psoriatic arthritis (PsA), psoriasis (Pso), ulcerative colitis (UC), Crohn's disease, systemic lupus erythematosus (SLE), asthma, and chronic obstructive Pulmonary disease (COPD).

在另一個實施方式中，本發明關於化合物A一水合物的結晶形式III用於製備在有需要的受試者中治療疾病、綜合症、病症或障礙的藥物，該疾病、綜合症、病症或障礙選自由以下項組成之群組：彌漫性大B細胞淋巴瘤(DLBCL)、外膜細胞淋巴瘤(MCL)、濾泡性淋巴瘤(FL)、黏膜相關淋巴組織(MALT)淋巴瘤、邊緣區淋巴瘤、慢性淋巴細胞性白血病(CLL)、小淋巴細胞淋巴瘤(SLL)、以及瓦爾登斯特倫巨球蛋白血症。在另外的實施方式中，該疾病、綜合症、病症或障礙係非何杰金氏淋巴瘤(NHL)。在另外的實施方式中，該非何杰金氏淋巴瘤(NHL)係B細胞NHL。 In another embodiment, the crystalline form III of compound A monohydrate of the present invention is used for the preparation of a medicament for the treatment of a disease, syndrome, disorder or disorder in a subject in need thereof, the disease, syndrome, disorder or The disorder is selected from the group consisting of: diffuse large B-cell lymphoma (DLBCL), adventitia cell lymphoma (MCL), follicular lymphoma (FL), mucosa-associated lymphoid tissue (MALT) lymphoma, marginal Regional lymphoma, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), and Waldenstrom's macroglobulinemia. In another embodiment, the disease, syndrome, condition or disorder is non-Hodgkin's lymphoma (NHL). In another embodiment, the non-Hodgkin's lymphoma (NHL) is a B cell NHL.

在另一個實施方式中，化合物A一水合物的結晶形式III用於在治療有需要的受試者中的障礙的方法中使用，該障礙選自由以下項組成之群組：彌漫性大B細胞淋巴瘤(DLBCL)、外膜細胞淋巴瘤(MCL)、濾泡性淋巴瘤(FL)、和黏膜相關淋巴組織(MALT)淋巴瘤、類風濕性關節炎(RA)、牛皮癬性關節炎(PsA)、牛皮癬(Pso)、潰瘍性結腸炎(UC)、克羅恩氏病、全身性紅斑狼瘡(SLE)、氣喘、以及慢性阻塞性肺病(COPD)。 In another embodiment, the crystalline form III of Compound A monohydrate is for use in a method of treating a disorder in a subject in need, the disorder being selected from the group consisting of: diffuse large B cells Lymphoma (DLBCL), adventitia cell lymphoma (MCL), follicular lymphoma (FL), and mucosal associated lymphoid tissue (MALT) lymphoma, rheumatoid arthritis (RA), psoriatic arthritis (PsA) ), psoriasis (Pso), ulcerative colitis (UC), Crohn’s disease, systemic lupus erythematosus (SLE), asthma, and chronic obstructive pulmonary disease (COPD).

在另一個實施方式中，化合物A一水合物的結晶形式III用於在治療有需要的受試者中的疾病、綜合症、病症或障礙的方法中使用，該疾病、綜合症、病症或障礙選自由以下項組成之群組：彌漫性大B細胞淋巴瘤(DLBCL)、外膜細胞淋巴瘤(MCL)、濾泡性淋巴瘤(FL)、黏膜相關淋巴組織(MALT)淋巴瘤、邊緣區淋巴瘤、慢性淋巴細胞性白血病(CLL)、小淋巴細胞淋巴瘤(SLL)、以及瓦爾登斯特倫巨球蛋白血症。在另外的實施方式中，在有需要的受試者中，該疾病、綜合症、病症或障礙係非何杰金氏淋巴瘤(NHL)。在另外的實施方式中，該非何杰金氏淋巴瘤(NHL)係B細胞NHL。 In another embodiment, the crystalline form III of Compound A monohydrate is used in a method of treating a disease, syndrome, disorder, or disorder in a subject in need, the disease, syndrome, disorder, or disorder Choose from the group consisting of: diffuse large B-cell lymphoma (DLBCL), adventitia cell lymphoma (MCL), follicular lymphoma (FL), mucosa associated lymphoid tissue (MALT) lymphoma, marginal zone Lymphoma, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), and Waldenstrom's macroglobulinemia. In another embodiment, in a subject in need, the disease, syndrome, condition or disorder is non-Hodgkin's lymphoma (NHL). In another embodiment, the non-Hodgkin's lymphoma (NHL) is a B cell NHL.

在另一個實施方式中，化合物A一水合物的結晶形式III用於在治療有需要的受試者中的障礙中使用，該障礙選自由以下項組成之群組：彌漫性大B細胞淋巴瘤(DLBCL)、外膜細胞淋巴瘤(MCL)、濾泡性淋巴瘤(FL)、和黏膜相關淋巴組織(MALT)淋巴瘤、類風濕性關節炎(RA)、牛皮癬性關節炎(PsA)、牛皮癬(Pso)、潰瘍性結腸炎(UC)、克羅恩氏病、全身性紅斑狼瘡(SLE)、氣喘、以及慢性阻塞性肺病(COPD)。 In another embodiment, the crystalline form III of Compound A monohydrate is for use in the treatment of a disorder in a subject in need, the disorder being selected from the group consisting of: diffuse large B-cell lymphoma (DLBCL), adventitia cell lymphoma (MCL), follicular lymphoma (FL), and mucosa associated lymphoid tissue (MALT) lymphoma, rheumatoid arthritis (RA), psoriatic arthritis (PsA), Psoriasis (Pso), ulcerative colitis (UC), Crohn's disease, systemic lupus erythematosus (SLE), asthma, and chronic obstructive pulmonary disease (COPD).

在另一個實施方式中，化合物A一水合物的結晶形式III用於在治療有需要的受試者中的疾病、綜合症、病症或障礙中使用，該疾病、綜合症、病症或障礙選自由以下項組成之群組：彌漫性大B細胞淋巴瘤(DLBCL)、外膜細胞淋巴瘤(MCL)、濾泡性淋巴瘤(FL)、黏膜相關淋巴組織(MALT)淋巴瘤、邊緣區淋巴瘤、慢性淋巴細胞性白血病(CLL)、小淋巴細胞淋巴瘤 (SLL)、以及瓦爾登斯特倫巨球蛋白血症。在另外的實施方式中，在有需要的受試者中，該疾病、綜合症、病症或障礙係非何杰金氏淋巴瘤(NHL)。在另外的實施方式中，該非何杰金氏淋巴瘤(NHL)係B細胞NHL。 In another embodiment, the crystalline form III of Compound A monohydrate is used in the treatment of a disease, syndrome, disorder, or disorder in a subject in need, the disease, syndrome, disorder, or disorder selected from Group consisting of: diffuse large B-cell lymphoma (DLBCL), adventitia cell lymphoma (MCL), follicular lymphoma (FL), mucosa-associated lymphoid tissue (MALT) lymphoma, marginal zone lymphoma , Chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), and Waldenstrom's macroglobulinemia. In another embodiment, in a subject in need, the disease, syndrome, condition, or disorder is non-Hodgkin's lymphoma (NHL). In another embodiment, the non-Hodgkin's lymphoma (NHL) is a B cell NHL.

在另一個實施方式中，化合物A一水合物的結晶形式III用於在治療有需要的受試者中的疾病、綜合症、病症或障礙中使用，其中所述疾病、綜合症、病症或障礙受MALT1的抑制的影響。 In another embodiment, the crystalline form III of Compound A monohydrate is for use in the treatment of a disease, syndrome, disorder, or disorder in a subject in need, wherein the disease, syndrome, disorder, or disorder Affected by the inhibition of MALT1.

在本發明的另一個實施方式中，化合物A一水合物的結晶形式III可以與一種或多種其他醫藥劑，更特別地與其他抗癌劑(例如化學治療劑、抗增殖劑或免疫調節劑)，或者與癌症療法中的佐劑(例如免疫抑制劑或抗炎劑)組合使用。 In another embodiment of the present invention, the crystalline form III of Compound A monohydrate can be combined with one or more other pharmaceutical agents, more particularly with other anticancer agents (such as chemotherapeutic agents, antiproliferative agents or immunomodulators). , Or used in combination with adjuvants in cancer therapy (such as immunosuppressive agents or anti-inflammatory agents).

將理解的是，可以對本發明的前述實施方式進行變型，同時仍然落入本發明的範圍內。除非另有說明，否則本說明書中揭露的每個特徵都可以由服務於相同、等同或類似目的的替代特徵代替。因此，除非另有說明，否則所揭露的每個特徵僅是一個通用系列的等同或類似特徵的一個實例。 It will be understood that the aforementioned embodiments of the present invention may be modified while still falling within the scope of the present invention. Unless otherwise specified, each feature disclosed in this specification can be replaced by an alternative feature serving the same, equivalent or similar purpose. Therefore, unless otherwise stated, each feature disclosed is only an example of a generic series of equivalent or similar features.

以上指示的實施方式的所有可能組合都視為包涵在本發明的範圍內。 All possible combinations of the above indicated embodiments are deemed to be included in the scope of the present invention.

現在參考以下實例，以非限制性方式說明本發明。 Reference is now made to the following examples to illustrate the present invention in a non-limiting manner.

實例 Instance

X射線粉末繞射(XRPD)分析在布魯克公司(Bruker)(D8 Advance)X射線粉末繞射儀上進行。將該化合物鋪展在單晶矽板上，並輕輕地壓成扁平且均勻的以進行測試。 X-ray powder diffraction (XRPD) analysis was performed on the Bruker (D8 Advance) X-ray powder diffraction instrument. The compound was spread on a single crystal silicon plate and gently pressed into a flat and uniform shape for testing.

使用以下方法在XRPD上運行樣品： Run the sample on XRPD using the following method:

管：Cu：K-α(λ=1.54056

Figure 109105620-A0202-12-0027-25
) Tube: Cu: K-α(λ=1.54056
Figure 109105620-A0202-12-0027-25
)

發生器：電壓：40kV；電流：40mA Generator: Voltage: 40kV; Current: 40mA

檢測器：PSD：LynxEye Detector: PSD: LynxEye

發散狹縫：0.60mm；入射側索勒狹縫(Soller Slit)：2.5° Divergence slit: 0.60mm; Soller Slit on the incident side: 2.5°

檢測器狹縫：10.50mm；防散射狹縫：7.10mm Detector slit: 10.50mm; anti-scatter slit: 7.10mm

繞射側索勒狹縫：2.5° Soler slit on the diffraction side: 2.5°

掃描類型：鎖定耦合 Scan type: lock coupling

掃描模式：連續掃描 Scan mode: continuous scan

掃描參數：掃描軸：2-θ/θ Scan parameters: scan axis: 2-θ/θ

掃描範圍：3°至50°；步長：0.02°。 Scan range: 3° to 50°; step size: 0.02°.

時間/步：0.12s Time/step: 0.12s

樣品轉速：60rpm Sample speed: 60rpm

掃描速率：10°/min Scan rate: 10°/min

熟悉該項技術者將認識到，繞射圖和峰位置通常基本上獨立於所使用的繞射儀以及是否利用特定的校準方法。通常，峰位置可以相差約±0.2°2θ或更小。每個特定繞射峰的強度(和相對強度)也可能隨各種因素的作用而變化，該等因素包括但不限於粒徑、方向、樣品純度等。然而，技術人員將能夠區分化合物A，水合物結晶形式I和化合物A，一水合物結晶形式III。 Those skilled in the art will recognize that the diffraction pattern and peak position are usually basically independent of the diffractometer used and whether a specific calibration method is used. Generally, the peak positions can differ by about ±0.2° 2θ or less. The intensity (and relative intensity) of each specific diffraction peak may also vary with various factors, including but not limited to particle size, direction, sample purity, and so on. However, the skilled person will be able to distinguish compound A, hydrate crystalline form I and compound A, monohydrate crystalline form III.

在配備有Hiden定量氣體分析單元的TA儀器Q5000 IR熱重量分析儀上進行熱重量分析(TGA)。將樣品盤去皮重後，將樣品置於來自TA儀器的標準鉑樣品盤中。將樣品從25°至300℃掃描，其中程式化加熱速率為20℃/min。 Thermogravimetric analysis (TGA) was performed on a TA instrument Q5000 IR thermogravimetric analyzer equipped with a Hiden quantitative gas analysis unit. After taring the sample pan, place the sample in the standard platinum sample pan from the TA instrument. The sample was scanned from 25° to 300°C with a programmed heating rate of 20°C/min.

使用表面測量系統Advantage-1動態蒸汽吸附裝置進行水分吸附分析(DVS)。藉由監測在25℃下，相對濕度在0%至95%範圍內的蒸汽吸附/解吸來評估水分曲線。水分曲線由2個循環的蒸汽吸附/解吸組成。 Use the surface measurement system Advantage-1 dynamic vapor adsorption device for moisture adsorption analysis (DVS). The moisture curve is evaluated by monitoring the adsorption/desorption of vapor at a relative humidity of 0% to 95% at 25°C. The moisture curve consists of 2 cycles of steam adsorption/desorption.

在帶有顯微ATR輔助設備的Nicolet 6700FT-IR光譜儀上進行紅外(IR)光譜法。 Infrared (IR) spectroscopy was performed on a Nicolet 6700FT-IR spectrometer with micro ATR auxiliary equipment.

實例1：1-(1-側氧基-1,2-二氫異喹啉-5-基)-5-(三氟甲基)-N-[2-(三氟甲基)吡啶-4-基]-1H-吡唑-4-甲醯胺(化合物A)水合物，結晶形式I的製備Example 1: 1-(1-Pendant oxy-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl) -N -[2-(trifluoromethyl)pyridine-4 -Yl]-1 H -pyrazole-4-carboxamide (compound A) hydrate, preparation of crystalline form I

化合物A水合物藉由類似於WO 2018/119036的實例158中所述的合成方法來製備。確認藉由該方法製備的化合物為水合物結晶形式，形式I。 Compound A hydrate was prepared by a synthetic method similar to that described in Example 158 of WO 2018/119036. It is confirmed that the compound prepared by this method is a hydrate crystal form, Form I.

使用X射線粉末繞射(XRPD)、差示掃描量熱法(DSC)、熱重量分析(TGA)、動態蒸汽吸附(DVS)、以及IR光譜法(圖7至圖12)來表徵形式I。 X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), dynamic vapor adsorption (DVS), and IR spectroscopy (Figures 7-12) were used to characterize Form I.

形式I的X射線粉末繞射圖(圖7)在鹵素不存在下顯示出不同的繞射峰，表明這係結晶產物。 The X-ray powder diffraction pattern of Form I (Figure 7) shows different diffraction peaks in the absence of halogen, indicating that this is a crystalline product.

表1提供了化合物A水合物形式I的XPRD(圖7)的峰列表和相對強度。 Table 1 provides the peak list and relative intensities of XPRD (Figure 7) of Compound A Hydrate Form I.

[表1]：

Figure 109105620-A0202-12-0029-6
[Table 1]:
Figure 109105620-A0202-12-0029-6

Figure 109105620-A0202-12-0030-7
Figure 109105620-A0202-12-0030-7

形式I的DSC曲線(圖8)在98.7℃(142J/g)下顯示出寬吸熱信號，其中起始溫度為66.3℃，這係由於水合物的脫水導致。在157.0℃(17J/g)下觀察到第二吸熱信號，其中起始溫度為145.2℃，並且對應於脫水形式的熔融。 The DSC curve of Form I (Figure 8) shows a broad endothermic signal at 98.7°C (142J/g), where the onset temperature is 66.3°C, which is caused by the dehydration of the hydrate. The second endothermic signal was observed at 157.0°C (17J/g), where the onset temperature was 145.2°C and corresponds to the melting of the dehydrated form.

形式I的TGA曲線(圖9)顯示，由於存在的溶劑(水)蒸發，從RT高至82℃的重量損失為4.7%。在82℃-122℃之間記錄到0.4%的重量損失，且該重量損失對應於溶劑的進一步蒸發。 The TGA curve of Form I (Figure 9) shows that the weight loss from RT up to 82°C is 4.7% due to the evaporation of the solvent (water) present. A weight loss of 0.4% was recorded between 82°C and 122°C and this weight loss corresponds to further evaporation of the solvent.

形式I的DVS質量變化圖(圖11)顯示，在初始乾燥步驟期間重量損失約為2.7%。該化合物在0-20% RH(相對濕度)的濕度範圍內快速吸附並解吸水(圖10和圖11)。根據大氣濕度，它最多可吸收4.1%-4.2%的水分(RH在0%-20%之間)，並在解吸循環期間完全乾燥。在20%-95% RH的濕度範圍內，該化合物緩慢並且可逆地進行吸附和解吸，其中有1.8%的水分吸附和解吸。DVS測試後獲得的級分的XRPD圖和IR光譜與起始材料相當。沒有觀察到固態形式改變的指示。 The DVS mass change graph of Form I (Figure 11) shows that the weight loss during the initial drying step is approximately 2.7%. The compound quickly adsorbs and desorbs water in the humidity range of 0-20% RH (relative humidity) (Figure 10 and Figure 11). Depending on the atmospheric humidity, it can absorb up to 4.1%-4.2% moisture (RH between 0%-20%), and is completely dry during the desorption cycle. In the humidity range of 20%-95% RH, the compound adsorbs and desorbs slowly and reversibly, and 1.8% of the water is adsorbed and desorbed. The XRPD pattern and IR spectrum of the fraction obtained after the DVS test are comparable to the starting material. No indication of a change in solid form was observed.

該數據表明形式I中的水合水鬆散結合，並且在RH為20%及更低時失去。 This data shows that the water of hydration in Form I is loosely bound and is lost at RH 20% and lower.

實例2：1-(1-側氧基-1,2-二氫異喹啉-5-基)-5-(三氟甲基)-N-[2-(三氟甲基)吡啶-4-基]-1H-吡唑-4-甲醯胺(化合物A)一水合物，形式III晶種材料的製備Example 2: 1-(1-Pendant oxy-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl) -N -[2-(trifluoromethyl)pyridine-4 -Yl]-1 H -pyrazole-4-carboxamide (compound A) monohydrate, preparation of form III seed material

將大約200mg由實例1獲得的化合物A，水合物形式I添加至400μl-800μl的乙酸乙酯或乙酸異丙酯中，並將所得懸浮液在60℃下攪拌5天。然後將該沈澱物過濾並在真空下於50℃乾燥24小時，以產出化合物A形式III的結晶一水合物。 Approximately 200 mg of compound A obtained in Example 1, hydrate form I was added to 400 μl-800 μl of ethyl acetate or isopropyl acetate, and the resulting suspension was stirred at 60° C. for 5 days. The precipitate was then filtered and dried under vacuum at 50°C for 24 hours to produce a crystalline monohydrate of Compound A, Form III.

實例3：1-(1-側氧基-1,2-二氫異喹啉-5-基)-5-(三氟甲基)-N-[2-(三氟甲基)吡啶-4-基]-1H-吡唑-4-甲醯胺(化合物A)一水合物，形式III的製備Example 3: 1-(1-Pendant oxy-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl) -N -[2-(trifluoromethyl)pyridine-4 -Yl]-1 H -pyrazole-4-carboxamide (compound A) monohydrate, preparation of form III

將藉由類似於WO 2018/119036的實例158中所述的合成方法的程序獲得的1-(1-側氧基-1,2-二氫異喹啉-5-基)-5-(三氟甲基)-N-[2-(三氟甲基)吡啶-4-基]-1H-吡唑-4-甲醯胺(100g)連同乙醇(150mL-170mL)和乙酸乙酯(80mL-100mL)一起充入燒瓶(R1)中。將獲得的混合物加熱至40°-50℃並攪拌0.5-2小時。然後添加水(4mL-7mL)，並藉由卡爾費歇爾(Karl Fischer)滴定測 量含水量。將R1的內容物溫熱至40°-55℃，並過濾至在40°-55℃預熱的第二燒瓶(R2)中。將R1在40°-50℃下用乙酸乙酯(80mL-100mL)沖洗，並將內容物過濾至R2中。在約20-40min內將正庚烷(340mL-410mL)充入R2中，維持40°-55℃。將獲得的溶液用1.9g-2.1g的化合物A一水合物形式III(獲得自實例2)進行晶種接種，並將獲得的混合物在40°-55℃攪拌4-8小時。在10-15小時內添加正庚烷(680-750mL)，維持40℃-55℃；將獲得的混合物在40°-55℃下再攪拌2-5小時，然後將其冷卻至20°-25℃，持續7-13小時。將懸浮液在20°-25℃下攪拌12h-18h，然後將其過濾並用正庚烷(180mL-250mL)洗滌。在真空下於45°-55℃乾燥15-22小時後，獲得了具有80%產率的1-(1-側氧基-1,2-二氫異喹啉-5-基)-5-(三氟甲基)-N-[2-(三氟甲基)吡啶-4-基]-1H-吡唑-4-甲醯胺一水合物(形式III)。 Will be obtained by the procedure similar to the synthetic method described in the example 158 of WO 2018/119036 1-(1-side oxy-1,2-dihydroisoquinolin-5-yl)-5-(tri Fluoromethyl) -N -[2-(trifluoromethyl)pyridin-4-yl]-1 H -pyrazole-4-carboxamide (100g) together with ethanol (150mL-170mL) and ethyl acetate (80mL -100mL) are filled into the flask (R1) together. The obtained mixture was heated to 40°-50°C and stirred for 0.5-2 hours. Then water (4mL-7mL) was added, and the water content was measured by Karl Fischer titration. Warm the contents of R1 to 40°-55°C and filter into a second flask (R2) preheated at 40°-55°C. R1 was rinsed with ethyl acetate (80 mL-100 mL) at 40°-50°C, and the contents were filtered into R2. Fill R2 with n-heptane (340mL-410mL) in about 20-40min and maintain 40°-55°C. The obtained solution was seeded with 1.9g-2.1g of compound A monohydrate form III (obtained from Example 2), and the obtained mixture was stirred at 40°-55°C for 4-8 hours. Add n-heptane (680-750mL) within 10-15 hours, maintain 40°-55°C; stir the obtained mixture at 40°-55°C for another 2-5 hours, then cool it to 20°-25 ℃ for 7-13 hours. The suspension was stirred at 20°-25°C for 12h-18h, then it was filtered and washed with n-heptane (180mL-250mL). After drying under vacuum at 45°-55°C for 15-22 hours, 1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-yl was obtained with 80% yield (trifluoromethyl) - N - [2- (trifluoromethyl) pyridin-4-yl] -1 H - pyrazole-4-acyl-amine monohydrate (form III).

實例3b：1-(1-側氧基-1,2-二氫異喹啉-5-基)-5-(三氟甲基)-N-[2-(三氟甲基)吡啶-4-基]-1H-吡唑-4-甲醯胺(化合物A)一水合物，形式III的製備Example 3b: 1-(1-Pendant oxy-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl) -N -[2-(trifluoromethyl)pyridine-4 -Yl]-1 H -pyrazole-4-carboxamide (compound A) monohydrate, preparation of form III

將藉由類似於WO 2018/119036的實例158中所述的合成方法的程序獲得的1-(1-側氧基-1,2-二氫異喹啉-5-基)-5-(三氟甲基)-N-[2-(三氟甲基)吡啶-4-基]-1H-吡唑-4-甲醯胺(25g)連同水(2.5mL-4.5mL)和異丙醇(IPA)(100mL)一起充入燒瓶(R1)中。將獲得的混合物加熱至50℃並攪拌0.5-2小時。將正庚烷(125mL)充入R1中。將獲得的溶液用500mg的化合物A一水合物形式III(獲得自實例2)進行晶種接種，並將獲得的混合物在50℃攪拌72小時。在12小時內添加正庚烷(275mL)，維持50℃；將獲得的混合物在50℃下再攪拌58小時，然後將其冷卻至20°-25℃，持續2小時。將懸浮液在20°-25℃下攪拌94h，然後將其過濾並用正庚烷(100mL)洗滌。在真空下於50℃乾燥24小時後，獲得了具有90%產率的1-(1-側氧基-1,2-二氫異喹啉-5-基)-5-(三氟甲基)-N-[2-(三氟甲基)吡啶-4-基]-1H-吡唑-4-甲醯胺一水合物(形式III)。 Will be obtained by the procedure similar to the synthetic method described in the example 158 of WO 2018/119036 1-(1-side oxy-1,2-dihydroisoquinolin-5-yl)-5-(tri Fluoromethyl) -N -[2-(trifluoromethyl)pyridin-4-yl]-1 H -pyrazole-4-carboxamide (25g) together with water (2.5mL-4.5mL) and isopropanol (IPA) (100 mL) was charged into the flask (R1) together. The obtained mixture was heated to 50°C and stirred for 0.5-2 hours. Charge n-heptane (125 mL) into R1. The obtained solution was seeded with 500 mg of compound A monohydrate form III (obtained from Example 2), and the obtained mixture was stirred at 50°C for 72 hours. N-heptane (275 mL) was added within 12 hours, maintaining 50°C; the obtained mixture was stirred at 50°C for another 58 hours, and then cooled to 20°-25°C for 2 hours. The suspension was stirred at 20°-25°C for 94 h, then it was filtered and washed with n-heptane (100 mL). After drying under vacuum at 50°C for 24 hours, 1-(1- pendant oxy-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl) with a yield of 90% ) - N - [2- (trifluoromethyl) pyridin-4-yl] -1 H - pyrazole-4-acyl-amine monohydrate (form III).

使用X射線粉末繞射(XRPD)、差示掃描量熱法(DSC)、熱重量分析(TGA)、動態蒸汽吸附(DVS)、以及IR光譜法-參見圖1至圖6來表徵形式III。 X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), dynamic vapor adsorption (DVS), and IR spectroscopy were used-see Figures 1 to 6 to characterize Form III.

形式III的X射線粉末繞射圖(圖1)在鹵素不存在下顯示出不同的繞射峰，表明該化合物作為結晶產物存在。 The X-ray powder diffraction pattern of Form III (Figure 1) shows different diffraction peaks in the absence of halogen, indicating that the compound exists as a crystalline product.

表2提供了化合物A一水合物形式III的XPRD(圖1)的峰列表和相對強度。 Table 2 provides the peak list and relative intensities of XPRD (Figure 1) of Compound A monohydrate Form III.

[表2]：

Figure 109105620-A0202-12-0033-8
[Table 2]:
Figure 109105620-A0202-12-0033-8

Figure 109105620-A0202-12-0034-9
Figure 109105620-A0202-12-0034-9

形式III的DSC曲線(圖2)顯示出結晶產物的塌陷和液化為吸熱信號，其中起始溫度為142℃，最高溫度為158℃(145.9J/g)。 The DSC curve of Form III (Figure 2) shows that the collapse and liquefaction of the crystalline product are endothermic signals, where the starting temperature is 142°C and the highest temperature is 158°C (145.9J/g).

形式III的TGA曲線(圖3)顯示，由於結合溶劑的蒸發，從RT高至180℃的總重量損失為3.9%。 The TGA curve of Form III (Figure 3) shows that the total weight loss from RT up to 180°C is 3.9% due to the evaporation of the binding solvent.

藉由動態蒸汽吸附(DVS)分析評估了形式III的吸濕特徵。從圖4和圖5中的DVS圖可以看出，形式III係非吸濕的。與形式I不同，形式III在RH(低相對濕度)條件下不會失水。DVS測試後獲得的級分的XRPD圖和IR光譜與起始材料相當。沒有觀察到固態形式改變的指示。 The moisture absorption characteristics of Form III were evaluated by dynamic vapor adsorption (DVS) analysis. As can be seen from the DVS diagrams in Figures 4 and 5, Form III is non-hygroscopic. Unlike Form I, Form III does not lose water under RH (low relative humidity) conditions. The XRPD pattern and IR spectrum of the fraction obtained after the DVS test are comparable to the starting material. No indication of a change in solid form was observed.

實例4：化合物A一水合物形式III的物理穩定性研究Example 4: Study on the physical stability of compound A monohydrate form III

測試了相對於失水或吸水，化合物A一水合物形式III的物理穩定性。 The physical stability of compound A monohydrate form III relative to water loss or water absorption was tested.

對於初始研究，將一水合物形式III的0.5g樣品置於雙層防靜電無色LDPE袋中並密封。 For the initial study, a 0.5 g sample of monohydrate form III was placed in a double antistatic colorless LDPE bag and sealed.

對於長期研究(1個月和3個月後的穩定性)，將一水合物形式III的1.5g樣品置於雙層防靜電無色LDPE袋中並密封。將樣品在30±2℃/75%±5% RH和40±2℃/75%±5% RH下在紙板桶中儲存。 For long-term studies (stability after 1 month and 3 months), 1.5 g samples of monohydrate form III were placed in a double antistatic colorless LDPE bag and sealed. The samples are stored in cardboard drums at 30±2°C/75%±5% RH and 40±2°C/75%±5% RH.

對於光穩定性研究，將1.5g一水合物形式III置於培養皿中，並鋪展成不超過3mm厚的一層。將培養皿用石英蓋玻片覆蓋，並用石蠟膜密封。根據ICH Q1B選項2(ICH協調的三方指導原則，穩定性測試：新藥品和產品的光穩定性測試，Q1B，步驟4版本，1996年11月6日)進行了光穩定性測試。將光穩定性樣品儲存在發出可見光和UV-A光的分開的燈下，以使總暴露分別不少於120萬勒克斯小時和200瓦時/m2。 For light stability studies, 1.5 g of monohydrate form III was placed in a petri dish and spread into a layer no more than 3 mm thick. Cover the petri dish with a quartz cover glass and seal with paraffin film. The light stability test was carried out according to ICH Q1B Option 2 ( Tripartite Guidelines for ICH Coordination, Stability Test: Light Stability Test of New Drugs and Products, Q1B, Step 4 Version, November 6, 1996 ). The photostability samples are stored under separate lamps emitting visible light and UV-A light so that the total exposure is not less than 1.2 million lux hours and 200 Wh/m 2 respectively .

每個樣品的含水量係使用蒸發的庫侖定量卡爾．費歇爾法測定的，該方法依照美國藥典(USP<921>方法IC；最近出現在Pharmacopeial Forum[藥典論壇]第38卷(1)；頁面資訊USP42/NF37-7092)和European Pharmacopeia[歐洲藥典]2.5.32(10.0版)。 The water content of each sample is quantified by Coulomb of evaporation. Fischer method is determined according to the United States Pharmacopeia (USP<921> Method IC; recently appeared in Pharmacopeial Forum [Pharmacopoeia Forum] Vol. 38 (1); page information USP42/NF37-7092) and European Pharmacopeia [ European Pharmacopeia] ] 2.5.32 (version 10.0).

結果(表3)表明，一水合物形式III係非吸濕的。 The results (Table 3) indicate that the monohydrate form III is non-hygroscopic.

[表3]：

Figure 109105620-A0202-12-0035-10
[table 3]:
Figure 109105620-A0202-12-0035-10

儘管本文已經顯示和描述了本發明的較佳的實施方式，但是熟悉該項技術者很清楚，該等實施方式僅是作為實例提供的。在不偏離本發明的情況下，多種變型、改變和替換係熟悉該項技術者容易想到的。應理解，在實踐本發明時可以使用本文所述的本發明實施方式的各種替代方案，並且該等申請專利範圍範圍內的實施方式及其等同物由此被覆蓋。 Although the preferred embodiments of the present invention have been shown and described herein, it is clear to those skilled in the art that these embodiments are only provided as examples. Without departing from the present invention, many modifications, changes and substitutions are easily conceivable by those skilled in the art. It should be understood that various alternatives to the embodiments of the present invention described herein can be used in practicing the present invention, and the embodiments and their equivalents within the scope of the patent application are covered thereby.

Claims (14)

1-(1-側氧基-1,2-二氫異喹啉-5-基)-5-(三氟甲基)-N-[2-(三氟甲基)吡啶-4-基]-1H-吡唑-4-甲醯胺(化合物A)一水合物的一種結晶形式： 1-(1-Pendant oxy-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl) -N -[2-(trifluoromethyl)pyridin-4-yl] A crystalline form of -1 H -pyrazole-4-methamide (Compound A) monohydrate:
Figure 109105620-A0202-13-0001-11
Figure 109105620-A0202-13-0001-11
 其中該結晶形式係形式III，其產生X射線粉末繞射圖，該X射線粉末繞射圖包含在16.4、23.7和25.7°2θ±0.2°2θ處的峰。 The crystalline form is Form III, which produces an X-ray powder diffraction pattern that includes peaks at 16.4, 23.7, and 25.7°2θ±0.2°2θ. 如申請專利範圍第1項所述之結晶形式，其中該X射線粉末繞射圖進一步包含在13.6、17.9、22.6、24.5、25.2和27.1°2θ±0.2°2θ處的峰。 The crystalline form described in item 1 of the scope of patent application, wherein the X-ray powder diffraction pattern further includes peaks at 13.6, 17.9, 22.6, 24.5, 25.2, and 27.1°2θ±0.2°2θ. 如申請專利範圍第1或2項所述之結晶形式，其中該X射線粉末繞射圖進一步包含選自8.3、8.6、11.5、14.0、15.4、17.5、19.7、22.0、22.2、24.0和29.9°2θ±0.2°2θ的至少一個峰。 The crystalline form as described in item 1 or 2 of the scope of the patent application, wherein the X-ray powder diffraction pattern further comprises selected from 8.3, 8.6, 11.5, 14.0, 15.4, 17.5, 19.7, 22.0, 22.2, 24.0 and 29.9°2θ At least one peak of ±0.2°2θ. 如申請專利範圍第1或2項所述之結晶形式，其進一步特徵在於基本上如圖1所示的X射線粉末繞射圖。 The crystalline form described in item 1 or 2 of the scope of the patent application is further characterized by an X-ray powder diffraction pattern as shown in FIG. 1. 如申請專利範圍第1或2項所述之結晶形式，其進一步特徵在於差示掃描量熱法熱譜圖，該差示掃描量熱法熱譜圖包含起始溫度為約142℃和/或峰值溫度為約158℃的吸熱。 The crystalline form described in item 1 or 2 of the scope of the patent application is further characterized by a differential scanning calorimetry thermogram, which includes an initial temperature of about 142°C and/or The peak temperature is an endotherm of about 158°C. 一種藥物組成物，該藥物組成物包含如前述申請專利範圍中任一項所述之結晶形式、以及藥學上可接受的載體、藥學上可接受的賦形劑、和藥學上可接受的稀釋劑中的至少一種。 A pharmaceutical composition comprising a crystalline form as described in any one of the aforementioned patent applications, a pharmaceutically acceptable carrier, a pharmaceutically acceptable excipient, and a pharmaceutically acceptable diluent At least one of them. 如申請專利範圍第6項所述之藥物組成物，其中該組成物係固體口服劑型。 The pharmaceutical composition according to item 6 of the scope of patent application, wherein the composition is a solid oral dosage form. 如申請專利範圍第6項所述之藥物組成物，其中該組成物係糖漿劑、酏劑、懸浮液。 The pharmaceutical composition described in item 6 of the scope of patent application, wherein the composition is a syrup, an elixir, or a suspension. 一種如申請專利範圍第1至5項中任一項所述之結晶形式用於製備治療有需要的受試者中的疾病、綜合症、障礙或病症的藥物之用途，其中所述疾病、綜合症、病症或障礙受MALT1的抑制的影響。 The use of a crystalline form as described in any one of items 1 to 5 of the scope of the patent application for the preparation of a medicine for the treatment of a disease, syndrome, disorder or condition in a subject in need, wherein the disease, comprehensive Symptoms, symptoms or disorders are affected by the inhibition of MALT1. 如申請專利範圍第9項所述之用途，其中所述疾病、綜合症、病症或障礙選自癌症和免疫性疾病。 The use according to item 9 of the scope of patent application, wherein the disease, syndrome, disorder or disorder is selected from cancer and immune disease. 一種呈如申請專利範圍第1至5項中任一項所述之結晶形式的化合物，該化合物用於在治療有需要的受試者中的疾病、綜合症、病症或障礙中使用，其中所述疾病、綜合症、病症或障礙受MALT1的抑制的影響。 A compound in a crystalline form as described in any one of items 1 to 5 of the scope of the patent application for use in the treatment of a disease, syndrome, disorder, or disorder in a subject in need, wherein The disease, syndrome, disorder or disorder is affected by the inhibition of MALT1. 一種用於製備如申請專利範圍第1至5項中任一項所述之結晶形式的方法，該方法包括重結晶化合物A的步驟，其中該重結晶包括以下步驟： A method for preparing the crystalline form as described in any one of items 1 to 5 in the scope of the patent application, the method comprising the step of recrystallizing compound A, wherein the recrystallization comprises the following steps: a)將化合物A或其水合物或溶劑化物添加至乙酸乙酯和乙醇的混合物中，並加熱至從約30℃至溶劑回流溫度範圍內的溫度； a) Add compound A or its hydrate or solvate to the mixture of ethyl acetate and ethanol, and heat to a temperature in the range from about 30°C to the reflux temperature of the solvent; b)將水添加至該混合物中並過濾出任何沈澱物，維持所述溫度； b) Add water to the mixture and filter out any precipitate, maintaining the temperature; c)將正庚烷添加至該混合物中，用結晶形式III進行晶種接種，並維持所述溫度；以及 c) adding n-heptane to the mixture, seeding with crystalline form III, and maintaining the temperature; and d)冷卻至室溫，以產出如申請專利範圍第1至5項中任一項所述之結晶形式的沈澱物； d) Cool down to room temperature to produce the precipitate in the crystalline form as described in any one of items 1 to 5 in the scope of the patent application; 其中水的量相對於溶劑的總重量為從約0.1w/w%至約3.0w/w%。 The amount of water is from about 0.1 w/w% to about 3.0 w/w% relative to the total weight of the solvent. 如申請專利範圍第12項所述之方法，其中該溫度為從約40℃至約55℃。 The method according to claim 12, wherein the temperature is from about 40°C to about 55°C. 一種用於製備如申請專利範圍第1至5項中任一項所述之結晶形式的方法，該方法包括重結晶化合物A的步驟，其中該重結晶包括以下步驟： A method for preparing the crystalline form as described in any one of items 1 to 5 in the scope of the patent application, the method comprising the step of recrystallizing compound A, wherein the recrystallization comprises the following steps: a)將化合物A或其水合物或溶劑化物添加至水和異丙醇的混合物中，並加熱至從約30℃至溶劑回流溫度範圍內的溫度； a) Add compound A or its hydrate or solvate to the mixture of water and isopropanol, and heat to a temperature in the range of from about 30°C to the reflux temperature of the solvent; b)將正庚烷添加至該混合物中，用結晶形式III進行晶種接種，並維持所述溫度；以及 b) adding n-heptane to the mixture, seeding with crystalline form III, and maintaining the temperature; and c)冷卻至室溫，以產出如申請專利範圍第1至5項中任一項所述的結晶形式的沈澱物； c) Cool down to room temperature to produce a precipitate in the crystalline form as described in any one of items 1 to 5 in the scope of the patent application; 其中水的量相對於溶劑的總重量為從約1.0w/w%至約6.0w/w%。 The amount of water is from about 1.0 w/w% to about 6.0 w/w% relative to the total weight of the solvent.
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